Force field based molecular structure and conformer generation

A method for generating conformational variations of three-dimensional (3D) molecular structures of organic molecules, the method including steps of

• receiving one or more representations of a selected molecule, said representations identifying assignment of 3D atomic positions and atomic bonds;
• identifying one or more ring systems in the selected molecule;
• performing one or more biophysical transformations on the ring systems, said biophysical transformations representing natural physical adjustment of one or more of the atomic positions with respect to a geometric or topological feature of the selected molecule;
• selecting one or more conformational variants in response to a measure of molecular energy;
• and
• repeating the steps of performing, producing, and selecting until a termination condition is reached;
• wherein the steps of selecting are responsive to
• eliminating redundant conformational variants from ring system elaboration in response to thresholds on RMS deviation that depend on ring system size or upon user specification;
• eliminating redundant conformational variants from torsional elaboration in response to thresholds on RMS deviation that depend upon user specification;
• or
• compression of conformational pools in response to selection of maximally different conformational variants.

A method for generating conformational variations of three-dimensional (3D) molecular structures of organic molecules, the method including steps of

• receiving one or more representations of a selected molecule, said representations identifying assignment of 3D atomic positions and atomic bonds;
• identifying one or more ring systems in the selected molecule;
• performing one or more biophysical transformations on the ring systems, said biophysical transformations representing natural physical adjustment of one or more of the atomic positions with respect to a geometric or topological feature of the selected molecule;
• selecting one or more conformational variants in response to a measure of molecular energy;
• and
• repeating the steps of performing, producing, and selecting until a termination condition is reached;
• wherein the ring systems include at least one macrocyclic structure having a connected ring structure of size nine or more,
• wherein the macrocyclic structure includes a torsional group of four atoms, the central two having a bond defining a twisting axis, a third atom defining an anchor, and a fourth atom defining a twistable atom;
• wherein the biophysical transformation includes a ring twist, the ring twist including rotating the twistable atom relative to the twisting axis, while the anchor atom maintains its position relative to the twisting axis;
• wherein the biophysical transformation includes performing the ring twist and conducting energy minimization with respect to a force field.

A method for generating three-dimensional (3D) molecular structures for conformational candidates of organic molecules, the method including steps of

• assigning initial atomic coordinates in response to molecular connectivity;
• refining those coordinates to minimize molecular energy while adhering to constraints upon molecular configuration;
• selecting candidate molecular structures in response to a measure of molecular energy and an assessment of congruence with specified molecular configuration;
• and
• repeating the steps of assigning initial atomic coordinates, refining those coordinates, and selecting candidate molecular structures, until a termination condition is reached;
• wherein the steps of assigning initial atomic coordinates include steps of
• computing initial approximate atomic positions by modeling each atom as a tetrahedron and by using approximate bond lengths and torsional choices to avoid energetically unfavorable configurations;
• wherein the steps of refining those coordinates include steps of
• assigning initial equal atomic partial charges,
• refining the initial positions using force field minimization including force field terms that include bond length, bond angle, and electrostatic terms,
• imposing force field terms to enforce specified chirality at tetrahedral centers, followed by energy minimization,
• imposing force field terms to enforce specified double-bond configurations along with all torsional terms, followed by energy minimization, and
• removing special configurational force field terms, assigning partial charges using a standard method, and minimizing the energy using all standard force field terms;
• repeating the preceding steps with alternative initial atomic coordinate assignments;
• and
• wherein the steps of selecting candidate molecular structures include steps of
• collecting the conformational variants so generated and evaluating each for configurational correctness and satisfaction of a maximum energy cutoff,
• terminating the repetition of steps when a fixed number of conformers meet the evaluation criteria or when a maximal number of repetitions has occurred, and
• producing the atomic coordinates of the conformer with lowest energy that passed the configurational correctness criteria.