Energy sampling against biomolecular ensembles has been of significant interest for several decades. Given the intricate nature of the internal energies of a biomolecular system, the multi-dimensional integral of the partition function is analytically inaccessible. This has lead to the development and application of numerical approximations for molecular ensemble sampling and partition function calculation. Unfortunately, these methods are often quite slow and computationally expensive. We have addressed the sampling problem by using a fast, novel methodology termed “Movable Type” (MT) which is conceptually analogous to the way the movable type printing press works. By separating the inter/intra-molecular energy into pair potentials, the MT method simulates the molecular energies through pair potential sampling and (re)combination. In the MT algorithm, we have devised rules to progressively decompose a molecular system into components (as the printing forme) with independent integrals over pairwise distances between the components. In this study, the MT algorithm is validated against several benchmark sets demonstrating that it is competitive with other, much slower methods in the prediction of the free energy of ligand binding, small molecule conformational free energy surface search, and protein:ligand docking. Since the method works in seconds (vs. hours or days for conventional methods), the investigator can use the method to quickly study protein:ligand binding on the free energy surface.

Movable type method: A fast, free energy method for scoring, docking, and conformational search

255th National Meeting (2018)

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