Abstract
Background: Empirical binding models have previously been investigated for the energetics of protein complexation (Delta G models) and for the influence of mutations on complexation (i.e. differences between wild-type and mutant complexes, Delta Delta G models). We construct binding models to directly compare these processes, which have generally been studied separately.
Results: Although reasonable fit models were found for both Delta G and Delta Delta G 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 Delta G models. However this Delta G model does not fit well to the data for binding differences upon mutation. Burial of non-polar area is weighted down in fitting of Delta Delta G 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 Delta G and Delta Delta G binding models.
Conclusion: We conclude that solvent accessible area, based on modelled mutant structures, is a poor correlate for Delta Delta G upon mutation. A simple volume-based, rather than solvent accessibility-based, model is constructed for Delta G and Delta Delta G 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.