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Comparing pairwise‐additive and many‐body generalized Born models for acid/base calculations and protein design
Author(s) -
Villa Francesco,
Mig David,
Polydorides Savvas,
Simonson Thomas
Publication year - 2017
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.24898
Subject(s) - pairwise comparison , protein design , solvent , monte carlo method , chemistry , computational chemistry , boundary (topology) , statistical physics , materials science , computer science , mathematics , protein structure , physics , mathematical analysis , organic chemistry , biochemistry , statistics , artificial intelligence
Generalized Born (GB) solvent models are common in acid/base calculations and protein design. With GB, the interaction between a pair of solute atoms depends on the shape of the protein/solvent boundary and, therefore, the positions of all solute atoms, so that GB is a many‐body potential. For compute‐intensive applications, the model is often simplified further, by introducing a mean, native‐like protein/solvent boundary, which removes the many‐body property. We investigate a method for both acid/base calculations and protein design that uses Monte Carlo simulations in which side chains can explore rotamers, bind/release protons, or mutate. The fluctuating protein/solvent dielectric boundary is treated in a way that is numerically exact (within the GB framework), in contrast to a mean boundary. Its originality is that it captures the many‐body character while retaining the residue‐pairwise complexity given by a fixed boundary. The method is implemented in the Proteus protein design software. It yields a slight but systematic improvement for acid/base constants in nine proteins and a significant improvement for the computational design of three PDZ domains. It eliminates a source of model uncertainty, which will facilitate the analysis of other model limitations. © 2017 Wiley Periodicals, Inc.