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Bayesian optimization for conformer generation.

ABSTRACT: Generating low-energy molecular conformers is a key task for many areas of computational chemistry, molecular modeling and cheminformatics. Most current conformer generation methods primarily focus on generating geometrically diverse conformers rather than finding the most probable or energetically lowest minima. Here, we present a new stochastic search method called the Bayesian optimization algorithm (BOA) for finding the lowest energy conformation of a given molecule. We compare BOA with uniform random search, and systematic search as implemented in Confab, to determine which method finds the lowest energy. Energetic difference, root-mean-square deviation, and torsion fingerprint deviation are used to quantify the performance of the conformer search algorithms. In general, we find BOA requires far fewer evaluations than systematic or uniform random search to find low-energy minima. For molecules with four or more rotatable bonds, Confab typically evaluates [Formula: see text] (median) conformers in its search, while BOA only requires [Formula: see text] energy evaluations to find top candidates. Despite using evaluating fewer conformers, 20-40% of the time BOA finds lower-energy conformations than a systematic Confab search for molecules with four or more rotatable bonds.

SUBMITTER: Chan L

PROVIDER: S-EPMC6528340 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Project description:ForceGen is a template-free, non-stochastic approach for 2D to 3D structure generation and conformational elaboration for small molecules, including both non-macrocycles and macrocycles. For conformational search of non-macrocycles, ForceGen is both faster and more accurate than the best of all tested methods on a very large, independently curated benchmark of 2859 PDB ligands. In this study, the primary results are on macrocycles, including results for 431 unique examples from four separate benchmarks. These include complex peptide and peptide-like cases that can form networks of internal hydrogen bonds. By making use of new physical movements ("flips" of near-linear sub-cycles and explicit formation of hydrogen bonds), ForceGen exhibited statistically significantly better performance for overall RMS deviation from experimental coordinates than all other approaches. The algorithmic approach offers natural parallelization across multiple computing-cores. On a modest multi-core workstation, for all but the most complex macrocycles, median wall-clock times were generally under a minute in fast search mode and under 2 min using thorough search. On the most complex cases (roughly cyclic decapeptides and larger) explicit exploration of likely hydrogen bonding networks yielded marked improvements, but with calculation times increasing to several minutes and in some cases to roughly an hour for fast search. In complex cases, utilization of NMR data to constrain conformational search produces accurate conformational ensembles representative of solution state macrocycle behavior. On macrocycles of typical complexity (up to 21 rotatable macrocyclic and exocyclic bonds), design-focused macrocycle optimization can be practically supported by computational chemistry at interactive time-scales, with conformational ensemble accuracy equaling what is seen with non-macrocyclic ligands. For more complex macrocycles, inclusion of sparse biophysical data is a helpful adjunct to computation.

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Bayesian optimization for conformer generation.

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