Improved Alchemical Free Energy Calculations with Optimized Smoothstep Softcore Potentials.

Journal of Chemical Theory and Computation
Tai-Sung LeeDarrin M York

Abstract

Progress in the development of GPU-accelerated free energy simulation software has enabled practical applications on complex biological systems and fueled efforts to develop more accurate and robust predictive methods. In particular, this work re-examines concerted (a.k.a., one-step or unified) alchemical transformations commonly used in the prediction of hydration and relative binding free energies (RBFEs). We first classify several known challenges in these calculations into three categories: endpoint catastrophes, particle collapse, and large gradient-jumps. While endpoint catastrophes have long been addressed using softcore potentials, the remaining two problems occur much more sporadically and can result in either numerical instability (i.e., complete failure of a simulation) or inconsistent estimation (i.e., stochastic convergence to an incorrect result). The particle collapse problem stems from an imbalance in short-range electrostatic and repulsive interactions and can, in principle, be solved by appropriately balancing the respective softcore parameters. However, the large gradient-jump problem itself arises from the sensitivity of the free energy to large values of the softcore parameters, as might be used in trying t...Continue Reading

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Citations

Feb 10, 2021·The Journal of Chemical Physics·Sheenam KhuttanEmilio Gallicchio
Apr 28, 2021·The Journal of Physical Chemistry. B·Hannah M BaumannDavid L Mobley
May 14, 2021·Journal of Chemical Theory and Computation·Joe Z WuEmilio Gallicchio
Nov 19, 2020·Journal of Chemical Theory and Computation·Ido Y Ben-ShalomMichael K Gilson
Dec 23, 2020·Journal of Chemical Theory and Computation·Anita de RuiterChris Oostenbrink
Aug 21, 2021·Journal of Chemical Information and Modeling·Drazen Petrov
Sep 17, 2020·Journal of Chemical Information and Modeling·Tai-Sung LeeDarrin M York
Aug 17, 2020·Journal of Chemical Information and Modeling·Gerhard KönigSereina Riniker
Aug 31, 2021·Frontiers in Molecular Biosciences·Edward KingRay Luo
Sep 4, 2021·Journal of Chemical Theory and Computation·Gerhard KönigSereina Riniker

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