This presentation will focus on recently developed methods for using QM and combined QM/MM to calculate binding free energies, determining pKa values, calculating solvation free energies, and distribution coefficients, using DFT and other ab initio methods. It is focused on methods to determine accurate free energies using a minimum number of quantum energy evaluations, allowing such calculations to be performed reasonably well on costly ab initio energy surfaces. Examples will focus on how these methods have been employed in multiple SAMPL competitions (SAMPL3 through SAMPL6), and such approaches been consistently among the top performers in these blind challenge competitions. The primary tools that allow this do be done on expensive ab initio energy surfaces are: contraints, action integrals (e.g. Action-CSA), enhanced sampling (e.g. SGLDrw), Non Boltzmann-Bennett ensemble methods (NBB), and the bookend methods for connecting a QM/MM free energy a similar MM free energy calculation. To improve these approaches, better MM surfaces are needed, and towards that end, progress in developing a new MPID (multipolar-induced dipole) force field that can provide better overlap between classical and quantum energy surfaces will be discussed.

Recent efforts in calculating free energy based properties using QM and QM/MM methods, and progress towards better MM methods to support more accurate QM/MM free energies

2019 Fall National Meeting

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