Insights into changes in binding affinity caused by disease mutations in protein-protein complexes

Abstract

Mutation of amino acid residues at protein-protein interfaces alters the binding affinity of protein-protein complexes and may lead to diseases. In this study, we have systematically analysed the relationship between the changes in binding affinity upon amino acid substitutions and the effect of mutations as disease-causing or neutral. We observed that a large proportion of disease-causing mutations decrease the binding affinity in all the considered datasets such as (i) experimentally known binding affinity and disease causing mutations, (ii) experimentally known binding affinity and predicted effects of mutations, and (iii) experimentally known disease causing mutations and predicted binding affinity. However, this relationship depends on the disease class, and the statistics indicate that factors other than binding affinity are also influencing the disease development. Further, structural analysis of protein-protein complexes revealed that disease-causing mutations are mainly attributed with the disruption of non-covalent interactions. In certain cancers, several mutations increase the binding affinity and they may have been selected to enhance cell survival and growth. Further, incorporating the effects of mutations on binding affinity in protein-protein interaction network studies may enable researchers to deduce the mechanisms of specific diseases and also help to identify novel drug targets.