segmentmodel.py 72.3 KB
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import numpy as np
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import random
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from arbdmodel import PointParticle, ParticleType, Group, ArbdModel
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from coords import rotationAboutAxis, quaternion_from_matrix, quaternion_to_matrix
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from nonbonded import *
from copy import copy, deepcopy
from nbPot import nbDnaScheme

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from scipy.special import erf
import scipy.optimize as opt
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from scipy import interpolate
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from CanonicalNucleotideAtoms import canonicalNtFwd, canonicalNtRev, seqComplement
from CanonicalNucleotideAtoms import enmTemplateHC, enmTemplateSQ, enmCorrectionsHC

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# import pdb
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"""
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TODO:
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 + fix handling of crossovers for atomic representation
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 + map to atomic representation
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    + add nicks
    - transform ssDNA nucleotides 
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    - shrink ssDNA
    - shrink dsDNA backbone
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    + make orientation continuous
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    - sequence
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    - handle circular dna
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 + ensure crossover bead potentials aren't applied twice 
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 + remove performance bottlenecks
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 - test for large systems
 - assign sequence
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 - ENM
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 - rework Location class 
 - remove recursive calls
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 - document
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 - add unit test of helices connected to themselves
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"""

class Location():
    """ Site for connection within an object """
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    def __init__(self, container, address, type_, on_fwd_strand = True):
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        ## TODO: remove cyclic references(?)
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        self.container = container
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        self.address = address  # represents position along contour length in segments
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        # assert( type_ in ("end3","end5") ) # TODO remove or make conditional
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        self.on_fwd_strand = on_fwd_strand
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        self.type_ = type_
        self.particle = None
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        self.connection = None
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        self.prev_in_strand = None
        self.next_in_strand = None
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        self.combine = None     # some locations might be combined in bead model 
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    def get_connected_location(self):
        if self.connection is None:
            return None
        else:
            return self.connection.other(self)

    def set_connection(self,connection):
        self.connection = connection # TODO weakref? 

    def __repr__(self):
        if self.on_fwd_strand:
            on_fwd = "on_fwd_strand"
        else:
            on_fwd = "on_rev_strand"
        # return "<Location in {} at contour {} {} with connection {}>".format( self.container.name, self.address, self.on_fwd_strand, self.connection )
        # return "<Location {} in {} at contour {} {} with connection {}>".format( self.type_, self.container.name, self.address, on_fwd, self.connection )
        return "<Location {}.{}[{:.2f},{:d}]>".format( self.container.name, self.type_, self.address, self.on_fwd_strand)
        
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class Connection():
    """ Abstract base class for connection between two elements """
    def __init__(self, A, B, type_ = None):
        assert( isinstance(A,Location) )
        assert( isinstance(B,Location) )
        self.A = A
        self.B = B
        self.type_ = type_
        
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    def other(self, location):
        if location is self.A:
            return self.B
        elif location is self.B:
            return self.A
        else:
            raise Exception("OutOfBoundsError")
        
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# class ConnectableElement(Transformable):
class ConnectableElement():
    """ Abstract base class """
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    ## TODO: eliminate mutable default arguments
    def __init__(self, connection_locations=[], connections=[]):
        ## TODO decide on names
        self.locations = self.connection_locations = connection_locations
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        self.connections = connections

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    def get_locations(self, type_=None, exclude=[]):
        locs = [l for l in self.connection_locations if (type_ is None or l.type_ == type_) and l.type_ not in exclude]
        counter = dict()
        for l in locs:
            if l in counter:
                counter[l] += 1
            else:
                counter[l] = 1
        assert( np.all( [counter[l] == 1 for l in locs] ) )
        return locs                

    def get_connections_and_locations(self, connection_type=None, exclude=[]):
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        """ Returns a list with each entry of the form:
            connection, location_in_self, location_in_other """
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        type_ = connection_type
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        ret = []
        for c in self.connections:
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            if (type_ is None or c.type_ == type_) and c.type_ not in exclude:
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                if   c.A.container is self:
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                    ret.append( [c, c.A, c.B] )
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                elif c.B.container is self:
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                    ret.append( [c, c.B, c.A] )
                else:
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                    import pdb
                    pdb.set_trace()
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                    raise Exception("Object contains connection that fails to refer to object")
        return ret

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    def _connect(self, other, connection):
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        ## TODO fix circular references        
        A,B = [connection.A, connection.B]
        A.connection = B.connection = connection
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        self.connections.append(connection)
        other.connections.append(connection)
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        l = A.container.locations
        if A not in l: l.append(A)
        l = B.container.locations
        if B not in l: l.append(B)
        

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    # def _find_connections(self, loc):
    #     return [c for c in self.connections if c.A == loc or c.B == loc]
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class SegmentParticle(PointParticle):
    def __init__(self, type_, position, name="A", segname="A", **kwargs):
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        self.name = name
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        self.contour_position = None
        PointParticle.__init__(self, type_, position, name=name, segname=segname, **kwargs)
        self.intrahelical_neighbors = []
        self.other_neighbors = []

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    # def get_contour_position(self,seg):
    #     assert( isinstance(seg,Segment) )
    #     if seg == self.parent:
    #         return self.contour_position
    #     else:
    #         ## TODO replace with something more elegant
    #         for c,A,B in self.parent.get_connections_and_locations():
    #             if A.particle is self and B.container is seg:
    #                 nt = np.abs( (self.contour_position - A.address)*(A.container.num_nts-1) )
    #                 if B.address < 0.5:
    #                     return B.address-nt/(seg.num_nts-1)
    #                 else:
    #                     return B.address+nt/(seg.num_nts-1)
    #         ## ERROR
    #         print("")
    #         for c,A,B in self.parent.get_connections_and_locations():
    #             print("  ",c.type_)
    #             print(A,B)
    #             print(A.particle,self)
    #             print(B.container,seg)
    #         print("")
    #         import pdb
    #         pdb.set_trace()
    #         raise Exception("Did not find location for particle {} in Segment {}".format(self,seg))

    def get_intrahelical_above(self):
        """ Returns bead directly above self """
        assert( len(self.intrahelical_neighbors) <= 2 )
        for b in self.intrahelical_neighbors:
            if b.get_contour_position(self.parent) > self.contour_position:
                return b

    def get_intrahelical_below(self):
        """ Returns bead directly below self """
        assert( len(self.intrahelical_neighbors) <= 2 )
        for b in self.intrahelical_neighbors:
            if b.get_contour_position(self.parent) < self.contour_position:
                return b
        

    def get_nt_position(self,seg):
        if seg == self.parent:
            return seg.contour_to_nt_pos(self.contour_position)
        else:
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            cl = [e for e in self.parent.get_connections_and_locations() if e[2].container is seg]
            dc = [(self.contour_position - A.address)**2 for c,A,B in cl]
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            if len(dc) == 0:
                pdb.set_trace()

            i = np.argmin(dc)
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            c,A,B = cl[i]
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            ## TODO: generalize, removing np.abs and conditional 
            delta_nt = np.abs( A.container.contour_to_nt_pos(self.contour_position - A.address) )
            B_nt_pos = seg.contour_to_nt_pos(B.address)
            if B.address < 0.5:
                return B_nt_pos-delta_nt
            else:
                return B_nt_pos+delta_nt

    def get_contour_position_old(self,seg):
        if seg == self.parent:
            return self.contour_position
        else:
            cl = [e for e in self.parent.get_connections_and_locations() in B.container is seg]
            dc = [(self.contour_position - A.address)**2 for c,A,B in e]

            if len(dc) == 0:
                pdb.set_trace()

            i = np.argmin(dc)

            nt = np.abs( (self.contour_position - A.address)*(A.container.num_nts-1) )
            if B.address < 0.5:
                return seg.nt_pos_to_contour(B.address-nt)
            else:
                return seg.nt_pos_to_contour(B.address+nt)

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    def get_contour_position(self,seg):
        if seg == self.parent:
            return self.contour_position
        else:
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            nt_pos = self.get_nt_position(seg)
            return seg.nt_pos_to_contour(nt_pos)
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## TODO break this class into smaller, better encapsulated pieces
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class Segment(ConnectableElement, Group):

    """ Base class that describes a segment of DNA. When built from
    cadnano models, should not span helices """

    """Define basic particle types"""
    dsDNA_particle = ParticleType("D",
                                  diffusivity = 43.5,
                                  mass = 300,
                                  radius = 3,                 
                              )
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    orientation_particle = ParticleType("O",
                                        diffusivity = 100,
                                        mass = 300,
                                        radius = 1,
                                    )
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    # orientation_bond = HarmonicBond(10,2)
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    orientation_bond = HarmonicBond(30,1.5, rRange = (0,500) )
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    ssDNA_particle = ParticleType("S",
                                  diffusivity = 43.5,
                                  mass = 150,
                                  radius = 3,                 
                              )

    def __init__(self, name, num_nts, 
                 start_position = np.array((0,0,0)),
                 end_position = None, 
                 segment_model = None):

        Group.__init__(self, name, children=[])
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        ConnectableElement.__init__(self, connection_locations=[], connections=[])
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        self.resname = name
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        self.start_orientation = None
        self.twist_per_nt = 0

        self.beads = [c for c in self.children] # self.beads will not contain orientation beads

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        self._bead_model_generation = 0    # TODO: remove?
        self.segment_model = segment_model # TODO: remove?

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        self.num_nts = int(num_nts)
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        if end_position is None:
            end_position = np.array((0,0,self.distance_per_nt*num_nts)) + start_position
        self.start_position = start_position
        self.end_position = end_position

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        ## Set up interpolation for positions
        a = np.array([self.start_position,self.end_position]).T
        tck, u = interpolate.splprep( a, u=[0,1], s=0, k=1)
        self.position_spline_params = tck
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        self.sequence = None
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    def clear_all(self):
        Group.clear_all(self)  # TODO: use super?
        self.beads = []
        for c,loc,other in self.get_connections_and_locations():
            loc.particle = None
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    def contour_to_nt_pos(self,contour_pos):
        return contour_pos*(self.num_nts-1)
    def nt_pos_to_contour(self,nt_pos):
        return nt_pos/(self.num_nts-1)

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    def contour_to_position(self,s):
        p = interpolate.splev( s, self.position_spline_params )
        if len(p) > 1: p = np.array(p).T
        return p

    def contour_to_tangent(self,s):
        t = interpolate.splev( s, self.position_spline_params, der=1 )
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        t = (t / np.linalg.norm(t,axis=0))
        return t.T
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    def contour_to_orientation(self,s):
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        assert( isinstance(s,float) or isinstance(s,int) or len(s) == 1 )   # TODO make vectorized version
        orientation = None
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        if self.start_orientation is not None:
            # axis = self.start_orientation.dot( np.array((0,0,1)) )
            if self.quaternion_spline_params is None:
                axis = self.contour_to_tangent(s)
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                orientation = rotationAboutAxis( axis, self.twist_per_nt*self.contour_to_nt_pos(s), normalizeAxis=True )
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            else:
                q = interpolate.splev( s, self.quaternion_spline_params )
                if len(q) > 1: q = np.array(q).T # TODO: is this needed?
                orientation = quaternion_to_matrix(q)
        return orientation
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    def get_contour_sorted_connections_and_locations(self,type_):
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        sort_fn = lambda c: c[1].address
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        cl = self.get_connections_and_locations(type_)
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        return sorted(cl, key=sort_fn)
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    def randomize_unset_sequence(self):
        bases = list(seqComplement.keys())
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        bases = ['T']        ## FOR DEBUG
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        if self.sequence is None:
            self.sequence = [random.choice(bases) for i in range(self.num_nts)]
        else:
            assert(len(self.sequence) == self.num_nts) # TODO move
            for i in range(len(self.sequence)):
                if self.sequence[i] is None:
                    self.sequence[i] = random.choice(bases)
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    def _get_num_beads(self, max_basepairs_per_bead, max_nucleotides_per_bead ):
        raise NotImplementedError

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    def _generate_one_bead(self, contour_position, nts):
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        raise NotImplementedError

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    def _generate_atomic_nucleotide(self, contour_position, is_fwd, seq):
        """ Seq should include modifications like 5T, T3 Tsinglet; direction matters too """

        # print("Generating nucleotide at {}".format(contour_position))
        
        pos = self.contour_to_position(contour_position)
        if self.local_twist:
            orientation = self.contour_to_orientation(contour_position)
            ## TODO: move this code (?)
            if orientation is None:
                axis = self.contour_to_tangent(contour_position)
                angleVec = np.array([1,0,0])
                if axis.dot(angleVec) > 0.9: angleVec = np.array([0,1,0])
                angleVec = angleVec - angleVec.dot(axis)*axis
                angleVec = angleVec/np.linalg.norm(angleVec)
                y = np.cross(axis,angleVec)
                orientation = np.array([angleVec,y,axis]).T
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                ## TODOTODO: improve placement of ssDNA
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                # rot = rotationAboutAxis( axis, contour_position*self.twist_per_nt*self.num_nts, normalizeAxis=True )
                # orientation = rot.dot(orientation)
            else:
                orientation = orientation
                            
        else:
            raise NotImplementedError

        # key = self.sequence
        # if self.ntAt5prime is None and self.ntAt3prime is not None: key = "5"+key
        # if self.ntAt5prime is not None and self.ntAt3prime is None: key = key+"3"
        # if self.ntAt5prime is None and self.ntAt3prime is None: key = key+"singlet"

        key = seq
        if not is_fwd:
            nt_dict = canonicalNtFwd
        else:
            nt_dict = canonicalNtRev
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        atoms = nt_dict[ key ].generate() # TODO: clone?
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        atoms.orientation = orientation.dot(atoms.orientation)
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        atoms.position = pos

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        ## TODOTODO: scale positions, set beta
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        return atoms
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    def add_location(self, nt, type_, on_fwd_strand=True):
        ## Create location if needed, add to segment
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        c = self.nt_pos_to_contour(nt)
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        assert(c >= 0 and c <= 1)
        # TODO? loc = self.Location( address=c, type_=type_, on_fwd_strand=is_fwd )
        loc = Location( self, address=c, type_=type_, on_fwd_strand=on_fwd_strand )
        self.locations.append(loc)

    ## TODO? Replace with abstract strand-based model?
    def add_5prime(self, nt, on_fwd_strand=True):
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        self.add_location(nt,"5prime",on_fwd_strand)
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    def add_3prime(self, nt, on_fwd_strand=True):
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        self.add_location(nt,"3prime",on_fwd_strand)
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    def get_3prime_locations(self):
        return self.get_locations("3prime")
    
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    def get_5prime_locations(self):
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        ## TODO? ensure that data is consistent before _build_model calls
        return self.get_locations("5prime")
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    def iterate_connections_and_locations(self, reverse=False):
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        ## connections to other segments
        cl = self.get_contour_sorted_connections_and_locations()
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        if reverse:
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            cl = cl[::-1]
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        for c in cl:
            yield c
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    ## TODO rename
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    def get_strand_segment(self, nt_pos, is_fwd):
        """ Walks through locations, checking for crossovers """

        ## Iterate through locations
        locations = sorted(self.locations, key=lambda l:(l.address,not l.on_fwd_strand), reverse=(not is_fwd))
        for l in locations:
            pos = self.contour_to_nt_pos(l.address)

            ## DEBUG

            ## Skip locations encountered before our strand
            tol = 0.1
            if is_fwd:
                if pos-nt_pos <= tol: continue 
            elif pos-nt_pos >= -tol: continue

            ## Stop if we found the 3prime end
            if l.on_fwd_strand == is_fwd and l.type_ == "3prime":
                return pos, None, None, None

            ## Check location connections
            c = l.connection
            if c is None: continue
            B = c.other(l)            

            ## Found a location on the same strand?
            if l.on_fwd_strand == is_fwd:
                # print("  passing through",l)
                # print("from {}, connection {} to {}".format(contour_pos,l,B))
                Bpos = B.container.contour_to_nt_pos(B.address)
                return pos, B.container, Bpos, B.on_fwd_strand
                
            ## Stop at other strand crossovers so basepairs line up
            elif c.type_ == "crossover":
                # print("  pausing at",l)
                return pos, l.container, pos+(2*is_fwd-1), is_fwd

        raise Exception("Shouldn't be here")
        # print("Shouldn't be here")
        ## Made it to the end of the segment without finding a connection
        return 1*is_fwd, None, None, None


    def get_end_of_strand_old(self, contour_pos, is_fwd):
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        """ Walks through locations, checking for crossovers """

        ## Iterate through locations
        # for l in self.locations:
        def loc_iter():
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            locations = sorted(self.locations, key=lambda l:(l.address,not l.on_fwd_strand), reverse=(not is_fwd))
            # if is_fwd:
            for l in locations:
                yield l
            # else:
            #     for l in locations[::-1]:
            #         yield l
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        for l in loc_iter():
            # if l.particle is None:
            #     pos = l.address
            # else:
            #     pos = l.particle.get_contour_position()          
            pos = l.address

            ## DEBUG
            # if self.name == "1-0" and is_fwd == False:
            #     import pdb
            #     pdb.set_trace()

            ## Skip locations encountered before our strand
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            if is_fwd:
                if pos <= contour_pos: continue
            elif pos >= contour_pos: continue

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            # print("  ?",l)
            
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            ## Stop if we found the 3prime end
            if l.on_fwd_strand == is_fwd and l.type_ == "3prime":
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                return pos, None, None, None
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            ## Check location connections
            c = l.connection
            if c is None: continue
            B = c.other(l)            

            ## Found a location on the same strand?
            if l.on_fwd_strand == is_fwd:
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                # print("  passing through",l)
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                # print("from {}, connection {} to {}".format(contour_pos,l,B))
                return pos, B.container, B.address, B.on_fwd_strand
                
            ## Stop at other strand crossovers so basepairs line up
            elif c.type_ == "crossover":
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                # print("  pausing at",l)
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                # print("pausing at {}".format(l))
                return pos, l.container, pos, is_fwd

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        raise Exception("Shouldn't be here")
        # print("Shouldn't be here")
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        ## Made it to the end of the segment without finding a connection
        return 1*is_fwd, None, None, None
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    def get_nearest_bead(self, contour_position):
        if len(self.beads) < 1: return None
        cs = np.array([b.contour_position for b in self.beads]) # TODO: cache
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        # TODO: include beads in connections?
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        i = np.argmin((cs - contour_position)**2)

        return self.beads[i]
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    def get_all_consecutive_beads(self, number):
        assert(number >= 1)
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        ## Assume that consecutive beads in self.beads are bonded
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        ret = []
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        for i in range(len(self.beads)-number+1):
            tmp = [self.beads[i+j] for j in range(0,number)]
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            ret.append( tmp )
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        return ret   
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    def _add_bead(self,b,set_contour=False):
        if set_contour:
            b.contour_position = b.get_contour_position(self)
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        # assert(b.parent is None)
        if b.parent is not None:
            b.parent.children.remove(b)
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        self.add(b)
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        self.beads.append(b) # don't add orientation bead
        if "orientation_bead" in b.__dict__: # TODO: think of a cleaner approach
            o = b.orientation_bead
            o.contour_position = b.contour_position
            if o.parent is not None:
                o.parent.children.remove(o)
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            self.add(o)
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            self.add_bond(b,o, Segment.orientation_bond, exclude=True)

    def _rebuild_children(self, new_children):
        # print("_rebuild_children on %s" % self.name)
        old_children = self.children
        old_beads = self.beads
        self.children = []
        self.beads = []
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        if True:
            print("WARNING: DEBUG")
            tmp = []
            for c in new_children:
                if c not in tmp:
                    tmp.append(c)
            new_children = tmp

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        for b in new_children:
            self.beads.append(b)
            self.children.append(b)
            if "orientation_bead" in b.__dict__: # TODO: think of a cleaner approach
                self.children.append(b.orientation_bead)
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        # tmp = [c for c in self.children if c not in old_children]
        # assert(len(tmp) == 0)
        # tmp = [c for c in old_children if c not in self.children]
        # assert(len(tmp) == 0)
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        assert(len(old_children) == len(self.children))
        assert(len(old_beads) == len(self.beads))
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    def _generate_beads(self, bead_model, max_basepairs_per_bead, max_nucleotides_per_bead):
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        """ Generate beads (positions, types, etcl) and bonds, angles, dihedrals, exclusions """
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        ## TODO: decide whether to remove bead_model argument
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        ##       (currently unused)
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        ## First find points between-which beads must be generated
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        # conn_locs = self.get_contour_sorted_connections_and_locations()
        # locs = [A for c,A,B in conn_locs]
        # existing_beads = [l.particle for l in locs if l.particle is not None]
        existing_beads = {l.particle for l in self.locations if l.particle is not None}
        existing_beads = sorted( list(existing_beads), key=lambda b: b.get_contour_position(self) )

        
        if len(existing_beads) != len(set(existing_beads)):
            pdb.set_trace()
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        for b in existing_beads:
            assert(b.parent is not None)

        ## Add ends if they don't exist yet
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        ## TODOTODO: test 1 nt segments?
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        if len(existing_beads) == 0 or existing_beads[0].get_contour_position(self) > 0:
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            if len(existing_beads) > 0:            
                assert(existing_beads[0].get_nt_position(self) > 1.5)

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            b = self._generate_one_bead(0, 0)
            existing_beads = [b] + existing_beads
        if existing_beads[-1].get_contour_position(self) < 1:
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            # assert((1-existing_beads[0].get_contour_position(self))*(self.num_nts-1) > 1.5)
            assert(self.num_nts-1-existing_beads[0].get_nt_position(self) > 1.5)
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            b = self._generate_one_bead(1, 0)
            existing_beads.append(b)
        assert(len(existing_beads) > 1)

        ## Walk through existing_beads, add beads between
        tmp_children = []       # build list of children in nice order
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        last = None
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        for I in range(len(existing_beads)-1):
            eb1,eb2 = [existing_beads[i] for i in (I,I+1)]
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            if eb1 is eb2:
                pdb.set_trace()
            assert( eb1 is not eb2 )
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            # print(" %s working on %d to %d" % (self.name, eb1.position[2], eb2.position[2]))
            e_ds = eb2.get_contour_position(self) - eb1.get_contour_position(self)
            num_beads = self._get_num_beads( e_ds, max_basepairs_per_bead, max_nucleotides_per_bead )
            ds = e_ds / (num_beads+1)
            nts = ds*self.num_nts
            eb1.num_nts += 0.5*nts
            eb2.num_nts += 0.5*nts

            ## Add beads
            if eb1.parent == self:
                tmp_children.append(eb1)

            s0 = eb1.get_contour_position(self)
            if last is not None:
                last.intrahelical_neighbors.append(eb1)
                eb1.intrahelical_neighbors.append(last)
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                assert(len(last.intrahelical_neighbors) <= 2)
                assert(len(eb1.intrahelical_neighbors) <= 2)
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            last = eb1
            for j in range(num_beads):
                s = ds*(j+1) + s0
                b = self._generate_one_bead(s,nts)

                last.intrahelical_neighbors.append(b)
                b.intrahelical_neighbors.append(last)
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                assert(len(last.intrahelical_neighbors) <= 2)
                assert(len(b.intrahelical_neighbors) <= 2)
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                last = b
                tmp_children.append(b)

        last.intrahelical_neighbors.append(eb2)
        eb2.intrahelical_neighbors.append(last)
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        assert(len(last.intrahelical_neighbors) <= 2)
        assert(len(eb2.intrahelical_neighbors) <= 2)
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        if eb2.parent == self:
            tmp_children.append(eb2)
        self._rebuild_children(tmp_children)
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    def _regenerate_beads(self, max_nts_per_bead=4, ):
        ...
    

class DoubleStrandedSegment(Segment):

    """ Class that describes a segment of ssDNA. When built from
    cadnano models, should not span helices """

    def __init__(self, name, num_nts, start_position = np.array((0,0,0)),
                 end_position = None, 
                 segment_model = None,
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                 local_twist = False,
                 num_turns = None,
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                 start_orientation = None):
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        self.helical_rise = 10.44
        self.distance_per_nt = 3.4
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        Segment.__init__(self, name, num_nts, 
                         start_position,
                         end_position, 
                         segment_model)

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        self.local_twist = local_twist
        if num_turns is None:
            num_turns = float(num_nts) / self.helical_rise
        self.twist_per_nt = float(360 * num_turns) / num_nts

        if start_orientation is None:
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            start_orientation = np.eye(3) # np.array(((1,0,0),(0,1,0),(0,0,1)))
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        self.start_orientation = start_orientation

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        self.nicks = []

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        self.start = self.start5 = Location( self, address=0, type_= "end5" )
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        self.start3 = Location( self, address=0, type_ = "end3", on_fwd_strand=False )
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        self.end = self.end3 = Location( self, address=1, type_ = "end3" )
        self.end5 = Location( self, address=1, type_= "end5", on_fwd_strand=False )
        for l in (self.start5,self.start3,self.end3,self.end5):
            self.locations.append(l)
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        ## Set up interpolation for azimuthal angles 
        a = np.array([self.start_position,self.end_position]).T
        tck, u = interpolate.splprep( a, u=[0,1], s=0, k=1)
        self.position_spline_params = tck
        
        ## TODO: initialize sensible spline for orientation
        self.quaternion_spline_params = None


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    ## Convenience methods
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    ## TODO: add errors if unrealistic connections are made
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    ## TODO: make connections automatically between unconnected strands
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    def connect_start5(self, end3, type_="intrahelical", force_connection=False):
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        if isinstance(end3, SingleStrandedSegment):
            end3 = end3.end3
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        self._connect_ends( self.start5, end3, type_, force_connection = force_connection )
    def connect_start3(self, end5, type_="intrahelical", force_connection=False):
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        if isinstance(end5, SingleStrandedSegment):
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            end5 = end5.start5
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        self._connect_ends( self.start3, end5, type_, force_connection = force_connection )
    def connect_end3(self, end5, type_="intrahelical", force_connection=False):
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        if isinstance(end5, SingleStrandedSegment):
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            end5 = end5.start5
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        self._connect_ends( self.end3, end5, type_, force_connection = force_connection )
    def connect_end5(self, end3, type_="intrahelical", force_connection=False):
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        if isinstance(end3, SingleStrandedSegment):
            end3 = end3.end3
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        self._connect_ends( self.end5, end3, type_, force_connection = force_connection )
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    def add_crossover(self, nt, other, other_nt, strands_fwd=[True,False]):
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        """ Add a crossover between two helices """
        ## Validate other, nt, other_nt
        ##   TODO

        ## Create locations, connections and add to segments
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        c = self.nt_pos_to_contour(nt)
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        assert(c >= 0 and c <= 1)
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        def get_loc(seg, address, on_fwd_strand):
            loc = None
            for l in seg.locations:
                if l.address == address and l.on_fwd_strand == on_fwd_strand:
                    assert(loc is None)
                    loc = l
            if loc is None:
                loc = Location( seg, address=address, type_="crossover", on_fwd_strand=on_fwd_strand )
            return loc

        loc = get_loc(self, c, strands_fwd[0])

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        c = other.nt_pos_to_contour(other_nt)
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        assert(c >= 0 and c <= 1)
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        other_loc = get_loc( other, c, strands_fwd[1] )
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        self._connect(other, Connection( loc, other_loc, type_="crossover" ))
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    ## Real work
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    def _connect_ends(self, end1, end2, type_, force_connection):
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        ## TODO remove self?
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        ## validate the input
        for end in (end1, end2):
            assert( isinstance(end, Location) )
            assert( end.type_ in ("end3","end5") )
        assert( end1.type_ != end2.type_ )
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        ## Create and add connection
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        end1.container._connect( end2.container, Connection( end1, end2, type_=type_ ) )
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    def _get_num_beads(self, contour, max_basepairs_per_bead, max_nucleotides_per_bead):
        return int(contour*self.num_nts // max_basepairs_per_bead)
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    def _generate_one_bead(self, contour_position, nts):
        pos = self.contour_to_position(contour_position)
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        if self.local_twist:
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            orientation = self.contour_to_orientation(contour_position)
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            if orientation is None:
                print("WARNING: local_twist is True, but orientation is None; using identity")
                orientation = np.eye(3)
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            opos = pos + orientation.dot( np.array((Segment.orientation_bond.r0,0,0)) )
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            o = SegmentParticle( Segment.orientation_particle, opos, nts,
                                 num_nts=nts, parent=self )
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            bead = SegmentParticle( Segment.dsDNA_particle, pos, name="DNA",
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                                    num_nts=nts, parent=self, 
                                    orientation_bead=o,
                                    contour_position=contour_position )
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        else:
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            bead = SegmentParticle( Segment.dsDNA_particle, pos, name="DNA",
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                                    num_nts=nts, parent=self,
                                    contour_position=contour_position )
        self._add_bead(bead)
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        return bead
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class SingleStrandedSegment(Segment):

    """ Class that describes a segment of ssDNA. When built from
    cadnano models, should not span helices """

    def __init__(self, name, num_nts, start_position = np.array((0,0,0)),
                 end_position = None, 
                 segment_model = None):

        self.distance_per_nt = 5
        Segment.__init__(self, name, num_nts, 
                         start_position,
                         end_position, 
                         segment_model)

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        self.start = self.start5 = Location( self, address=0, type_= "end5" ) # TODO change type_?
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        self.end = self.end3 = Location( self, address=1, type_ = "end3" )
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        for l in (self.start5,self.end3):
            self.locations.append(l)
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    def connect_3end(self, end5, force_connection=False):
        self._connect_end( end5,  _5_to_3 = False, force_connection = force_connection )

    def connect_5end(self, end3, force_connection=False):
        self._connect_end( end3,  _5_to_3 = True, force_connection = force_connection )

    def _connect_end(self, other, _5_to_3, force_connection):
        assert( isinstance(other, Location) )
        if _5_to_3 == True:
            my_end = self.end5
            assert( other.type_ == "end3" )
        else:
            my_end = self.end3
            assert( other.type_ == "end5" )

        self._connect( other.container, Connection( my_end, other, type_="intrahelical" ) )

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    def _get_num_beads(self, contour, max_basepairs_per_bead, max_nucleotides_per_bead):
        return int(contour*self.num_nts // max_nucleotides_per_bead)
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    def _generate_one_bead(self, contour_position, nts):
        pos = self.contour_to_position(contour_position)
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        b = SegmentParticle( Segment.ssDNA_particle, pos, 
                             name="NAS",
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                             num_nts=nts, parent=self,
                             contour_position=contour_position )
        self._add_bead(b)
        return b
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class StrandInSegment(Group):
    """ Class that holds atomic model, maps to segment """
    
    def __init__(self, segment, start, end, is_fwd):
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        """ start/end should be provided expressed in nt coordinates, is_fwd tuples """
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        Group.__init__(self)
        self.num_nts = 0
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        # self.sequence = []
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        self.segment = segment
        self.start = start
        self.end = end
        self.is_fwd = is_fwd

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        nts = np.abs(end-start)+1
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        self.num_nts = int(round(nts))
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        assert( np.abs(self.num_nts-nts) < 1e-5 )
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        # print(" Creating {}-nt StrandInSegment in {} from {} to {} {}".format(self.num_nts, segment.name, start, end, is_fwd))

    def get_sequence(self):
        """ return 5-to-3 """
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        # TODOTODO test
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        seg = self.segment
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        nt0 = self.start # seg.contour_to_nt_pos(self.start)
        assert( np.abs(nt0 - round(nt0)) < 1e-5 )
        nt0 = int(round(nt0))
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        assert( (self.end-self.start) >= 0 or not self.is_fwd )
        if self.is_fwd:
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            # return [seqComplement[seg.sequence[nt]] for nt in range(nt0,nt0+self.num_nts)]
            return [seg.sequence[nt] for nt in range(nt0,nt0+self.num_nts)]
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        else:
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            return [seqComplement[seg.sequence[nt]] for nt in range(nt0,nt0-self.num_nts,-1)]
    
    def get_contour_points(self):
        c0,c1 = [self.segment.nt_pos_to_contour(p) for p in (self.start,self.end)]
        return np.linspace(c0,c1,self.num_nts)
            
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class Strand(Group):
    """ Class that holds atomic model, maps to segments """
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    def __init__(self, segname = None):
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        Group.__init__(self)
        self.num_nts = 0
        self.children = self.strand_segments = []
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        self.segname = segname

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    ## TODO disambiguate names of functions
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    def add_dna(self, segment, start, end, is_fwd):
        """ start/end should be provided expressed as contour_length, is_fwd tuples """
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        if not (segment.contour_to_nt_pos(np.abs(start-end)) > 0.9):
            pdb.set_trace()
        for s in self.strand_segments:
            if s.segment == segment and s.is_fwd == is_fwd:
                assert( s.start not in (start,end) )
                assert( s.end not in (start,end) )
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        s = StrandInSegment( segment, start, end, is_fwd )
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        self.add( s )
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        self.num_nts += s.num_nts

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    def set_sequence(self,sequence):
        ## validate input
        assert( np.all( [i in ('A','T','C','G') for i in sequence] ) )

        ## set sequence on each segment
        for s in self.children:
            seg = s.segment
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            # TODOTODO
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            ...

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        ...

    # def get_sequence(self):
    #     sequence = []
    #     for ss in self.strand_segments:
    #         sequence.extend( ss.get_sequence() )

    #     assert( len(sequence) >= self.num_nts )
    #     ret = ["5"+sequence[0]] +\
    #           sequence[1:-1] +\
    #           [sequence[-1]+"3"]
    #     assert( len(ret) == self.num_nts )
    #     return ret

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    def generate_atomic_model(self):
        last = None
        resid = 1
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        strand_segment_count = 0
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        for s in self.strand_segments:
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            strand_segment_count += 1
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            seg = s.segment
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            contour = s.get_contour_points()
            assert(s.end != s.start)
            assert(np.linalg.norm( seg.contour_to_position(contour[-1]) - seg.contour_to_position(contour[0]) ) > 0.1)
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            for c,seq in zip(contour,s.get_sequence()):
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                if last is None:
                    seq = "5"+seq
                if strand_segment_count == len(s.strand_segments) and c == 1:
                    seq = seq+"3"

                nt = seg._generate_atomic_nucleotide( c, s.is_fwd, seq )
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                # if s.is_fwd:                    
                # else:
                #     nt = seg._generate_atomic_nucleotide( c, s.is_fwd, "A" )
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                s.add(nt)
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                ## Join last basepairs
                if last is not None:
                    o3,c3,c4,c2,h3 = [last.atoms_by_name[n] 
                                      for n in ("O3'","C3'","C4'","C2'","H3'")]
                    p,o5,o1,o2,c5 = [nt.atoms_by_name[n] 
                                     for n in ("P","O5'","O1P","O2P","C5'")]
                    self.add_bond( o3, p, None )
                    self.add_angle( c3, o3, p, None )
                    for x in (o5,o1,o2):
                        self.add_angle( o3, p, x, None )
                        self.add_dihedral(c3, o3, p, x, None )
                    for x in (c4,c2,h3):
                        self.add_dihedral(x, c3, o3, p, None )
                    self.add_dihedral(o3, p, o5, c5, None)
                nt.__dict__['resid'] = resid
                resid += 1
                last = nt
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    def update_atomic_orientations(self,default_orientation):
        last = None
        resid = 1
        for s in self.strand_segments:
            seg = s.segment
            contour = s.get_contour_points()
            for c,seq,nt in zip(contour,s.get_sequence(),s.children):

                orientation = seg.contour_to_orientation(c)
                ## TODO: move this code (?)
                if orientation is None:
                    axis = seg.contour_to_tangent(c)
                    angleVec = np.array([1,0,0])
                    if axis.dot(angleVec) > 0.9: angleVec = np.array([0,1,0])
                    angleVec = angleVec - angleVec.dot(axis)*axis
                    angleVec = angleVec/np.linalg.norm(angleVec)
                    y = np.cross(axis,angleVec)
                    orientation = np.array([angleVec,y,axis]).T

                nt.orientation = orientation.dot(default_orientation) # this one should be correct

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class SegmentModel(ArbdModel):
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    def __init__(self, segments=[], local_twist=True, escapable_twist=True,
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                 max_basepairs_per_bead=7,
                 max_nucleotides_per_bead=4,
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                 dimensions=(1000,1000,1000), temperature=291,
                 timestep=50e-6, cutoff=50, 
                 decompPeriod=10000, pairlistDistance=None, 
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                 nonbondedResolution=0,DEBUG=0):
        self.DEBUG = DEBUG
        if DEBUG > 0: print("Building ARBD Model")
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        ArbdModel.__init__(self,segments,
                           dimensions, temperature, timestep, cutoff, 
                           decompPeriod, pairlistDistance=None,
                           nonbondedResolution=0)

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        # self.max_basepairs_per_bead = max_basepairs_per_bead     # dsDNA
        # self.max_nucleotides_per_bead = max_nucleotides_per_bead # ssDNA
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        self.children = self.segments = segments

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        self._bonded_potential = dict() # cache for bonded potentials
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        self._generate_bead_model( max_basepairs_per_bead, max_nucleotides_per_bead, local_twist, escapable_twist)
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        self.useNonbondedScheme( nbDnaScheme )

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    def get_connections(self,type_=None,exclude=[]):
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        """ Find all connections in model, without double-counting """
        added=set()
        ret=[]
        for s in self.segments:
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            items = [e for e in s.get_connections_and_locations(type_,exclude=exclude) if e[0] not in added]
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            added.update([e[0] for e in items])
            ret.extend( items )
        return ret
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    def _recursively_get_beads_within_bonds(self,b1,bonds,done=[]):
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        ret = []
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        done = list(done)
        done.append(b1)
        if bonds == 0:
            return [[]]

        for b2 in b1.intrahelical_neighbors:
            if b2 in done: continue
            for tmp in self._recursively_get_beads_within_bonds(b2, bonds-1, done):
                ret.append( [b2]+tmp )
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        return ret

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    def _get_intrahelical_beads(self,num=2):
        ## TODO: add check that this is not called before adding intrahelical_neighbors in _generate_bead_model

        assert(num >= 2)

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        ret = []
        for s in self.segments:
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            for b1 in s.beads:
                for bead_list in self._recursively_get_beads_within_bonds(b1, num-1):
                    assert(len(bead_list) == num-1)
                    if b1.idx < bead_list[-1].idx: # avoid double-counting
                        ret.append([b1]+bead_list)
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        return ret

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    def _get_intrahelical_angle_beads(self):
        return self._get_intrahelical_beads(num=3)
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    def _get_potential(self, type_, kSpring, d, max_potential = None):
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        key = (type_, kSpring, d, max_potential)
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        if key not in self._bonded_potential:
            if type_ == "bond":
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                self._bonded_potential[key] = HarmonicBond(kSpring,d, rRange=(0,500), max_potential=max_potential)
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            elif type_ == "angle":
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                self._bonded_potential[key] = HarmonicAngle(kSpring,d, max_potential=max_potential)
                # , resolution = 1, maxForce=0.1)
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            elif type_ == "dihedral":
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                self._bonded_potential[key] = HarmonicDihedral(kSpring,d, max_potential=max_potential)
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            else:
                raise Exception("Unhandled potential type '%s'" % type_)
        return self._bonded_potential[key]
    def get_bond_potential(self, kSpring, d):
        return self._get_potential("bond", kSpring, d)
    def get_angle_potential(self, kSpring, d):
        return self._get_potential("angle", kSpring, d)
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    def get_dihedral_potential(self, kSpring, d, max_potential=None):
        while d > 180: d-=360
        while d < -180: d+=360
        return self._get_potential("dihedral", kSpring, d, max_potential)
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    def _getParent(self, *beads ):
        if np.all( [b1.parent == b2.parent 
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                    for b1,b2 in zip(beads[:-1],beads[1:])] ):
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            return beads[0].parent
        else:
            return self

    def _get_twist_spring_constant(self, sep):
        """ sep in nt """
        kT = 0.58622522         # kcal/mol
        twist_persistence_length = 90  # set semi-arbitrarily as there is a large spread in literature
        ## <cos(q)> = exp(-s/Lp) = integrate( cos[x] exp(-A x^2), {x, 0, pi} ) / integrate( exp(-A x^2), {x, 0, pi} )
        ##   Assume A is small
        ## int[B_] :=  Normal[Integrate[ Series[Cos[x] Exp[-B x^2], {B, 0, 1}], {x, 0, \[Pi]}]/
        ##             Integrate[Series[Exp[-B x^2], {B, 0, 1}], {x, 0, \[Pi]}]]

        ## Actually, without assumptions I get fitFun below
        ## From http://www.annualreviews.org/doi/pdf/10.1146/annurev.bb.17.060188.001405
        ##   units "3e-19 erg cm/ 295 k K" "nm" =~ 73
        Lp = twist_persistence_length/0.34 

        fitFun = lambda x: np.real(erf( (4*np.pi*x + 1j)/(2*np.sqrt(x)) )) * np.exp(-1/(4*x)) / erf(2*np.sqrt(x)*np.pi) - np.exp(-sep/Lp)
        k = opt.leastsq( fitFun, x0=np.exp(-sep/Lp) )
        return k[0][0] * 2*kT*0.00030461742
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    """ Mapping between different resolution models """
    def _clear_beads(self):
        for s in self.segments:
            s.clear_all()
        self.clear_all(keep_children=True)
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        assert( len([b for b in self]) == 0 )
        locParticles = []
        # for c,A,B in self.get_connections():
        for s in self.segments:
            for c,A,B in s.get_connections_and_locations():
                for l in (A,B):
                    if l.particle is not None:
                        locParticles.append(A.particle)
        assert( len(locParticles) == 0 )
        assert( len([b for s in self.segments for b in s.beads]) == 0 )
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    def _update_segment_positions(self, bead_coordinates):
        """ Set new function for each segments functions
        contour_to_position and contour_to_orientation """
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        for s in self.segments:
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            cabs = s.get_connections_and_locations("intrahelical")
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            if np.any( [B.particle is None for c,A,B in cabs] ):
                print( "WARNING: none type found in connection, skipping" )
                cabs = [e for e in cabs if e[2].particle is not None]
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            beads = set(s.beads + [A.particle for c,A,B in cabs])
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            ## Add nearby beads
            for c,A,B in cabs:
                ## TODOTODO test?
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                filter_fn = lambda x: x is not None and x not in beads
                bs = list( filter( filter_fn, B.particle.intrahelical_neighbors ) )
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                beads.update(bs)
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                bs = list( filter( filter_fn, [n for b in bs for n in b.intrahelical_neighbors] ) )