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Comparison of free‐energy methods using a tripeptide‐water model system
Author(s) -
Maurer Manuela,
Hansen Niels,
Oostenbrink Chris
Publication year - 2018
Publication title -
journal of computational chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.907
H-Index - 188
eISSN - 1096-987X
pISSN - 0192-8651
DOI - 10.1002/jcc.25537
Subject(s) - tripeptide , thermodynamic integration , pairwise comparison , molecule , chemistry , usability , computational chemistry , molecular dynamics , thermodynamics , sampling (signal processing) , computer science , biological system , statistical physics , materials science , physics , amino acid , organic chemistry , biochemistry , biology , filter (signal processing) , human–computer interaction , artificial intelligence , computer vision
We investigate the ability of several free‐energy calculation methods to combine two alchemical changes. We use Bennett acceptance ratio (BAR), thermodynamic integration (TI), extended TI (X‐TI), and enveloping distribution sampling (EDS) to perturb a water molecule, which is restrained to an amino acid that is also being perturbed. In addition to these pairwise methods, we present two two‐dimensional approaches, EDS‐TI and two‐dimensional TI (2D‐TI). We compare feasibility, efficiency and usability of these methods in regard to our simple model system, which mimics the displacement of a water molecule in the active site of a protein on residue mutation. The correct treatment of structural water has been shown to greatly aid binding affinity calculations in some cases that remained elusive otherwise. This is of broad interest in, for example, drug design, and we conclude that thus far, the pairwise method BAR and also the newer X‐TI remain the most suitable methods to treat this problem as long as few end states are involved. © 2018 Wiley Periodicals, Inc.