Journal of Computational Chemistry
Journal of Computational Chemistry
5 years ago

Comparing pairwise-additive and many-body generalized Born models for acid/base calculations and protein design

Comparing pairwise-additive and many-body generalized Born models for acid/base calculations and protein design
David Mignon, Savvas Polydorides, Thomas Simonson, Francesco Villa
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. Monte Carlo with many-body generalized Born (or fluctuating dielectric boundary [FDB]) treats the fluctuating protein shape exactly, as opposed to a fixed, effective boundary (native environment approximation), yielding improved acid/base constants. For the NHREF PDZ domain, the similarity scores of designed sequences versus natural sequences (from Pfam) improves dramatically with FDB, to the same level as sequences designed with the Rosetta software.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/jcc.24898

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