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J Chem Theory Comput. 2018 Jun 12;14(6):3218-3227. doi: 10.1021/acs.jctc.8b00027. Epub 2018 May 8.

Estimating Atomic Contributions to Hydration and Binding Using Free Energy Perturbation.

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Theory of Condensed Matter Group, Cavendish Laboratory , University of Cambridge , 19 J J Thomson Avenue , Cambridge CB3 0HE , United Kingdom.
Department of Chemistry , University of Cambridge , Lensfield Road , Cambridge CB2 1EW , United Kingdom.


We present a general method called atom-wise free energy perturbation (AFEP), which extends a conventional molecular dynamics free energy perturbation (FEP) simulation to give the contribution to a free energy change from each atom. AFEP is derived from an expansion of the Zwanzig equation used in the exponential averaging method by defining that the system total energy can be partitioned into contributions from each atom. A partitioning method is assumed and used to group terms in the expansion to correspond to individual atoms. AFEP is applied to six example free energy changes to demonstrate the method. Firstly, the hydration free energies of methane, methanol, methylamine, methanethiol, and caffeine in water. AFEP highlights the atoms in the molecules that interact favorably or unfavorably with water. Finally AFEP is applied to the binding free energy of human immunodeficiency virus type 1 protease to lopinavir, and AFEP reveals the contribution of each atom to the binding free energy, indicating candidate areas of the molecule to improve to produce a more strongly binding inhibitor. FEP gives a single value for the free energy change and is already a very useful method. AFEP gives a free energy change for each "part" of the system being simulated, where part can mean individual atoms, chemical groups, amino acids, or larger partitions depending on what the user is trying to measure. This method should have various applications in molecular dynamics studies of physical, chemical, or biochemical phenomena, specifically in the field of computational drug discovery.

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