Substitution mutations in protein-protein interfaces can have a substantial effect on binding, which has consequences in basic and applied biomedical research. Experimental expression, purification, and affinity determination of protein complexes is an expensive and time-consuming means of evaluating the effect of mutations, making a fast and accurate in silico method highly desirable. When the structure of the wild type complex is known, it is possible to economically evaluate the effect of point mutations with knowledge based potentials which do not model backbone flexibility, but these have been validated only for single mutants. Substitution mutations tend to induce local conformational rearrangements only. Accordingly, ZEMu (Zone Equilibration of Mutants) flexibilizes only a small region around the site of mutation, then computes its dynamics under a physics-based force field. We validate with 1254 experimental mutants (with 1-15 simultaneous substitutions) in a wide variety of different protein environments (65 protein complexes), and obtain a significant improvement in the accuracy of predicted ΔΔG.
We share data for community use in validating ΔΔG prediction protocols and potentials.
We provide all you need to reproduce the results of our Dourado & Flores 2014, and our upcoming Dourado & Flores 2015 paper, or simply use our equilibrated structures to validate a ΔΔG prediction potential. The dataset is based on SKEMPI, but some data was removed for quality and other concerns; therefore the mutation set itself may be useful for validating new equilibration protocols as well.