Molecule.py

from rdkit import Chem
from rdkit.Chem import AllChem
from rdkit.Chem.rdchem import Mol
import numpy as np
import numpy.linalg as la
from numpy.typing import NDArray
import os
import sys
from dataclasses import dataclass
import argparse
from RingFinder import RingFinder
from typing import List

@dataclass
class Ellipse:
    center: NDArray
    square_matrix: NDArray
    eigen_values: NDArray
    eigen_vectors: NDArray
    axes_magnitudes: NDArray
    axes: NDArray
    points: NDArray
    atom_idxs: List[int]

@dataclass
class ProgramInput:
    expandAtom: bool
    smiles: str
    fragment: bool
    numberNeighbors: int
    mergeLength: int

@dataclass
class MoleculeOutput:
    mol: Mol
    ellipsis: [Ellipse]

def generate_3d_conformation(mol: Mol) -> Mol:
    mol = Chem.AddHs(mol)
    AllChem.EmbedMolecule(mol)
    AllChem.MMFFOptimizeMolecule(mol)
    return mol


def molecule_points(mol: Mol, expandAtom, atom_idxs=None) -> NDArray:
    conformer = mol.GetConformer()
    coordinates = []
    atoms = []
    if atom_idxs is None:
        atoms = mol.GetAtoms()
    else:
        for atom_idx in atom_idxs:
            atom = mol.GetAtomWithIdx(atom_idx)
            atoms.append(atom)


    for atom in atoms:
        x = atom.GetAtomicNum()
        if x > 1:
            index = atom.GetIdx()
            if expandAtom:
                coordinate = conformer.GetAtomPosition(index)
                r = Chem.GetPeriodicTable().GetRvdw(x)
                coordinate.x = coordinate.x + r;
                coordinates.append(coordinate)
                coordinate = conformer.GetAtomPosition(index)
                coordinate.x = coordinate.x - r;
                coordinates.append(coordinate)
                coordinate = conformer.GetAtomPosition(index)
                coordinate.y = coordinate.y + r;
                coordinates.append(coordinate)
                coordinate = conformer.GetAtomPosition(index)
                coordinate.y = coordinate.y - r;
                coordinates.append(coordinate)
                coordinate = conformer.GetAtomPosition(index)
                coordinate.z = coordinate.z + r;
                coordinates.append(coordinate)
                coordinate = conformer.GetAtomPosition(index)
                coordinate.z = coordinate.z - r;
                coordinates.append(coordinate)
            else:
                coordinate = conformer.GetAtomPosition(index)
                coordinates.append(coordinate)

    return np.asarray(coordinates)


# from https://gist.github.com/Gabriel-p/4ddd31422a88e7cdf953
def mvee(points, tol=0.0001) -> [NDArray,NDArray]:
    """
    Finds the ellipse equation in "center form"
    (x-c).T * A * (x-c) = 1
    """
    N, d = points.shape
    Q = np.column_stack((points, np.ones(N))).T
    err = tol+1.0
    u = np.ones(N)/N
    while err > tol:
        # assert u.sum() == 1 # invariant
        X = np.dot(np.dot(Q, np.diag(u)), Q.T)
        M = np.diag(np.dot(np.dot(Q.T, la.inv(X)), Q))
        jdx = np.argmax(M)
        step_size = (M[jdx]-d-1.0)/((d+1)*(M[jdx]-1.0))
        new_u = (1-step_size)*u
        new_u[jdx] += step_size
        err = la.norm(new_u-u)
        u = new_u
    c = np.dot(u, points)
    A = la.inv(np.dot(np.dot(points.T, np.diag(u)), points)
               - np.multiply.outer(c, c))/d
    return A, c
    
def quadratic_to_parametric(center: NDArray, A: NDArray) -> Ellipse:
    # eigenvalues and eigenvectors using SVD
    # see https://en.wikipedia.org/wiki/Singular_value_decomposition
    # and https://laurentlessard.com/teaching/cs524/slides/11%20-%20quadratic%20forms%20and%20ellipsoids.pdf
    # For square symmetric A = U.D.VT matrix U = V 
    # and Eigen values of A are singular values in D
    # Columns of U (rows of VT) are Eigen vectors of A
    U, D, VT = la.svd(A)
    axes_magnitudes = 1.0/np.sqrt(D)
    small = [x < 1 for x in axes_magnitudes]
    if all(small) == True:
        return ValueError
    # hack to multiply by row instead of column
    axes = VT * axes_magnitudes[:, np.newaxis]

    ellipse = Ellipse(center = center, square_matrix = A, eigen_values = D, eigen_vectors = U, axes_magnitudes = axes_magnitudes, axes = axes, points = None, atom_idxs=None)
    return ellipse


def print_pymol_ellipse(moleculeOutput: MoleculeOutput, base: str) -> None:
    mol = moleculeOutput.mol
    block = Chem.MolToMolBlock(mol)
    out_file = f'{base}.sdf'
    with open(out_file, 'wt') as fh:
        fh.write(block)
    full_sd_path = os.getcwd() + os.path.sep + out_file;

    py_script = f'{base}.py'
    with open(py_script, 'wt') as fh:
        fh.write('from pymol.cgo import *\n')
        fh.write("cmd.delete('all')\n")
        fh.write(f"cmd.load('{full_sd_path}')\n")
        for ellipse_idx, ellipse in enumerate(moleculeOutput.ellipsis):
            center = ellipse.center
            mag = ellipse.axes_magnitudes
            rot = ellipse.eigen_vectors
            drawCommand = f'tmp{ellipse_idx} = drawEllipsoid([0.85, 0.85, 1.00] '
            for i in range(3):
                drawCommand = drawCommand + f', {center[i]}'
            for i in range(3):
                drawCommand = drawCommand + f', {mag[i]}'
            for i in range(3):
                for j in range(3):
                    drawCommand = drawCommand + f', {rot[i][j]}'
            drawCommand = drawCommand + ')'
            fh.write(drawCommand)
            fh.write('\n')
            fh.write(f"cmd.load_cgo(tmp{ellipse_idx}, 'ellipsoid-cgo{ellipse_idx}')\n")
            fh.write(f"cmd.set('cgo_transparency', 0.5, 'ellipsoid-cgo{ellipse_idx}')\n")
            fh.write(f"obj{ellipse_idx} = [\n BEGIN, LINES, \n COLOR, 0, 1.0, 0, \n")
            # write axes
            for i in range(0,3):
                fh.write(f'VERTEX, {center[0]}, {center[1]}, {center[2]},\n')
                axis = ellipse.axes[i] + center
                fh.write(f'VERTEX, {axis[0]}, {axis[1]}, {axis[2]},\n')
            fh.write("END\n] \n")
            fh.write(f"cmd.load_cgo(obj{ellipse_idx},'axis{ellipse_idx}')\n")
            fh.write(f"obj{ellipse_idx} = [\n BEGIN, POINTS, \n COLOR, 1.0, 1.0, 0, \n")
            #write points
            for point in ellipse.points:
                fh.write(f'VERTEX, {point[0]}, {point[1]}, {point[2]},\n')
            fh.write("END\n ] \n")
            fh.write(f"cmd.load_cgo(obj{ellipse_idx},'points{ellipse_idx}'), \n")
    
    full_py_path = os.getcwd() + os.path.sep + py_script
    print(f'Pymol script {full_py_path}')

def find_ellipses(programInput: ProgramInput):
    
    mol = None
    if '\n' in programInput.smiles:
        mol = Chem.MolFromMolBlock(programInput.smiles)
    else:
        mol = Chem.MolFromSmiles(programInput.smiles)
        mol = generate_3d_conformation(mol)
    ellipsoids = []
    mol = Chem.RemoveAllHs(mol);
    
    if programInput.fragment == True:
        ringFinder = RingFinder(mol, programInput.numberNeighbors, programInput.mergeLength)
        rings = ringFinder.rings
        branches = ringFinder.branches 
        fragments = list(rings) 
        fragments.extend(branches)
        for fragment in fragments:
             # find points on ellipsoid
            points = molecule_points(mol, programInput.expandAtom, fragment)
            # find MVEE
            # Quadratic form defined by square symmetric matrix A and centered at centroid
            if len(points) > 1:
                A, center = mvee(points);
                ellipsoid = quadratic_to_parametric(center, A)
                ellipsoid.points = points
                ellipsoid.atom_idxs = fragment
                ellipsoids.append(ellipsoid)

    else:
        # find points on ellipsoid
        points = molecule_points(mol, programInput.expandAtom)
        # find MVEE
        # Quadratic form defined by square symmetric matrix A and centered at centroid
        A, center = mvee(points);
        ellipsoid = quadratic_to_parametric(center, A)
        ellipsoid.points = points
        ellipsoids.append(ellipsoid)


    output = MoleculeOutput(mol, ellipsoids)
    return output


if __name__ == '__main__':
    parser = argparse.ArgumentParser()
    parser.add_argument("--smiles")
    parser.add_argument("--expandAtom", action=argparse.BooleanOptionalAction)
    parser.add_argument("--fragment", action=argparse.BooleanOptionalAction)
    parser.add_argument("--numberNeighbors", nargs='?', const=1, type=int)
    parser.add_argument("--mergeLength", nargs='?', const=1, type=int)
    args = parser.parse_args()
    print(f'Smiles from arguments is {args.smiles}')
    print(f'expandAtom from arguments is {args.expandAtom}')
    smiles = args.smiles
    if not smiles:
        print('Using default smiles')
        smiles = 'Cc1c(cc([nH]1)C(=O)NC2CCN(CC2)c3ccc4ccccc4n3)Br'
        smiles = 'CC(C)C[C@H](NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CO)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CS)C(=O)O'
        # In the smiles a period is used to separate multiple molecules- so this smiles is 4 organic compounds and a bunch of salts
        # We can only deal with single molecules, so I've selected the first
        # smiles = 'CCCCC(=O)N(CC1=CC=C(C=C1)C2=CC=CC=C2C3=NN=N[N-]3)C(C(C)C)C(=O)[O-].CCCCC(=O)N(CC1=CC=C(C=C1)C2=CC=CC=C2C3=NN=N[N-]3)C(C(C)C)C(=O)[O-].CCOC(=O)C(C)CC(CC1=CC=C(C=C1)C2=CC=CC=C2)NC(=O)CCC(=O)[O-].CCOC(=O)C(C)CC(CC1=CC=C(C=C1)C2=CC=CC=C2)NC(=O)CCC(=O)[O-].O.O.O.O.O.[Na+].[Na+].[Na+].[Na+].[Na+].[Na+]'
        # smiles = 'CCCCC(=O)N(CC1=CC=C(C=C1)C2=CC=CC=C2C3=NN=N[N-]3)C(C(C)C)C(=O)[O-]'
    expandAtom = args.expandAtom
    fragment = args.fragment
    numberNeighbors = args.numberNeighbors
    mergeLength = args.mergeLength

    programInput = ProgramInput( expandAtom, smiles, fragment, numberNeighbors, mergeLength)
    output = find_ellipses(programInput)
   
    print_pymol_ellipse(output, 'out')