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.