A self-consistent structural perturbation approach for determining the magnitude and extent of allosteric coupling in proteins.

Elucidating the extent of energetic coupling between residues in single-domain proteins, which is a fundamental determinant of allostery, information transfer and folding cooperativity, has remained a grand challenge. While several sequence- and structure-based approaches have been proposed, a self-consistent description that is simultaneously compatible with unfolding thermodynamics is lacking. We recently developed a simple structural perturbation protocol that captures the changes in thermodynamic stabilities induced by point mutations within the protein interior. Here, we show that a fundamental residue-specific component of this perturbation approach, the coupling distance, is uniquely sensitive to the environment of a residue in the protein to a distance of ∼15 Å. With just the protein contact map as an input, we reproduce the extent of percolation of perturbations within the structure as observed in network analysis of intra-protein interactions, molecular dynamics simulations and NMR-observed changes in chemical shifts. Using this rapid protocol that relies on a single structure, we explain the results of statistical coupling analysis (SCA) that requires hundreds of sequences to identify functionally critical sectors, the propagation and dissipation of perturbations within proteins and the higher-order couplings deduced from detailed NMR experiments. Our results thus shed light on the possible mechanistic origins of signaling through the interaction network within proteins, the likely distance dependence of perturbations induced by ligands and post-translational modifications and the origins of folding cooperativity through many-body interactions.