Coevolutionary signals across protein lineages help capture multiple protein conformations

Significance We show that directly coupled evolutionary residue pairs provide a distinct footprint of conformational diversity in protein families. This is revealed as competing residue contacts unique to distinct configurations of proteins with multiple conformations. We demonstrate that combining this information with physical models of proteins is sufficient to uncover conformational diversity for several protein families. We discovered that such directly coupled residues not only allow us to accurately transition between apo and holo conformations but also help to uncover intermediate states that are not easily accessible to experimental or other computational methods. This enhanced sampling of the functional conformational space of proteins may have broad implications in protein structure determination and the design of ligands that can trap intermediate states. A long-standing problem in molecular biology is the determination of a complete functional conformational landscape of proteins. This includes not only proteins’ native structures, but also all their respective functional states, including functionally important intermediates. Here, we reveal a signature of functionally important states in several protein families, using direct coupling analysis, which detects residue pair coevolution of protein sequence composition. This signature is exploited in a protein structure-based model to uncover conformational diversity, including hidden functional configurations. We uncovered, with high resolution (mean ∼1.9 Å rmsd for nonapo structures), different functional structural states for medium to large proteins (200–450 aa) belonging to several distinct families. The combination of direct coupling analysis and the structure-based model also predicts several intermediates or hidden states that are of functional importance. This enhanced sampling is broadly applicable and has direct implications in protein structure determination and the design of ligands or drugs to trap intermediate states.

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