The role of coevolutionary signatures in protein interaction dynamics, complex inference, molecular recognition, and mutational landscapes.

Evolution imposes constraints at the interface of interacting biomolecules in order to preserve function or maintain fitness. This pressure may have a direct effect on the sequence composition of interacting biomolecules. As a result, statistical patterns of amino acid or nucleotide covariance that encode for physical and functional interactions are observed in sequences of extant organisms. In recent years, global pairwise models of amino acid and nucleotide coevolution from multiple sequence alignments have been developed and utilized to study molecular interactions in structural biology. In proteins, for which the energy landscape is funneled and minimally frustrated, a direct connection between the physical and sequence space landscapes can be established. Estimating coevolutionary information from sequences of interacting molecules has a broad impact in molecular biology. Applications include the accurate determination of 3D structures of molecular complexes, inference of protein interaction partners, models of protein-protein interaction specificity, the elucidation, and design of protein-nucleic acid recognition as well as the discovery of genome-wide epistatic effects. The current state of the art of coevolutionary analysis includes biomedical applications ranging from mutational landscapes and drug-design to vaccine development.