Volume-based solvation models out-perform area-based models in combined studies of wild-type and mutated protein-protein interfacesReportar como inadecuado

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BMC Bioinformatics

, 9:448

First Online: 21 October 2008Received: 11 June 2008Accepted: 21 October 2008


BackgroundEmpirical binding models have previously been investigated for the energetics of protein complexation ΔG models and for the influence of mutations on complexation i.e. differences between wild-type and mutant complexes, ΔΔG models. We construct binding models to directly compare these processes, which have generally been studied separately.

ResultsAlthough reasonable fit models were found for both ΔG and ΔΔG cases, they differ substantially. In a dataset curated for the absence of mainchain rearrangement upon binding, non-polar area burial is a major determinant of ΔG models. However this ΔG model does not fit well to the data for binding differences upon mutation. Burial of non-polar area is weighted down in fitting of ΔΔG models. These calculations were made with no repacking of sidechains upon complexation, and only minimal packing upon mutation. We investigated the consequences of more extensive packing changes with a modified mean-field packing scheme. Rather than emphasising solvent exposure with relatively extended sidechains, rotamers are selected that exhibit maximal packing with protein. This provides solvent accessible areas for proteins that are much closer to those of experimental structures than the more extended sidechain regime. The new packing scheme increases changes in non-polar burial for mutants compared to wild-type proteins, but does not substantially improve agreement between ΔG and ΔΔG binding models.

ConclusionWe conclude that solvent accessible area, based on modelled mutant structures, is a poor correlate for ΔΔG upon mutation. A simple volume-based, rather than solvent accessibility-based, model is constructed for ΔG and ΔΔG systems. This shows a more consistent behaviour. We discuss the efficacy of volume, as opposed to area, approaches to describe the energetic consequences of mutations at interfaces. This knowledge can be used to develop simple computational screens for binding in comparative modelled interfaces.

AbbreviationsASAAccessible Surface Area

PDBProtein Data Bank

PINTProtein-protein Interactions Database

ASEdbAlanine Scanning Energetics database

BPTIBovine Pancreatic Trypsin Inhibitor

FDPBFinite Difference Poisson-Boltzmann


FD-DHFinite Difference-Debye-Hückel

GRETLGNU Regression: Econometrics and Time-series Library.

Electronic supplementary materialThe online version of this article doi:10.1186-1471-2105-9-448 contains supplementary material, which is available to authorized users.

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Autor: Salim Bougouffa - Jim Warwicker

Fuente: https://link.springer.com/

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