Molecular dynamics simulations and statistical coupling analysis reveal functional coevolution network of oncogenic mutations in the CDKN2A–CDK6 complex

Coevolution between proteins is crucial for understanding protein–protein interaction. Simultaneous changes allow a protein complex to maintain its overall structural–functional integrity. In this study, we combined statistical coupling analysis (SCA) and molecular dynamics simulations on the CDK6–CDKN2A protein complex to evaluate coevolution between proteins. We reconstructed an inter-protein residue coevolution network, consisting of 37 residues and 37 interactions. It shows that most of the coevolved residue pairs are spatially proximal. When the mutations happened, the stable local structures were broken up and thus the protein interaction was decreased or inhibited, with a following increased risk of melanoma. The identification of inter-protein coevolved residues in the CDK6–CDKN2A complex can be helpful for designing protein engineering experiments.

► Coevolved residue pairs in CDK6–CDKN2A are spatially proximal.
► The failure to functionally compensate leads to the inhibition of the protein interaction.
► Correlated mutations between proteins provide insight into drug design.