Evolution shapes interaction patterns for epistasis and specific protein binding in a two-component signaling system

The elegant design of protein sequence/structure/function relationships arises from the interaction patterns between amino acid positions. A central question is how evolutionary forces shape the interaction patterns that encode long-range epistasis and binding specificity. Here, we combined family-wide evolutionary analysis of natural homologous sequences and structure-oriented evolution simulation for two-component signaling (TCS) system. The magnitude-frequency relationship of coupling conservation between positions manifests a power-law-like distribution and the positions with highly coupling conservation are sparse but distributed intensely on the binding surfaces and hydrophobic core. The structure-specific interaction pattern involves further optimization of local frustrations at or near the binding surface to adapt the binding partner. The construction of family-wide conserved interaction patterns and structure-specific ones demonstrates that binding specificity is modulated by both direct intermolecular interactions and long-range epistasis across the binding complex. Evolution sculpts the interaction patterns via sequence variations at both family-wide and structure-specific levels for TCS system. Protein binding plays an important role in the function and design of protein complexes, however, the relationships among protein sequences, structures, and interactions shaped by evolution remain underexplored. Here, the authors use computational simulations to study the binding specificity of a two-component system under protein sequence evolution and reveal that the binding specificity is modulated by both direct intermolecular interactions and long-range epistasis across the binding complex.