The allosteric lever: towards a principle of specific allosteric response (2311.12025v3)

Abstract: Allostery, the phenomenon by which the perturbation of a molecule at one site alters its behavior at a remote functional site, enables control over biomolecular function. Allosteric modulation is a promising avenue for drug discovery and is employed in the design of mechanical metamaterials. However, a general principle of allostery, i.e. a set of quantitative and transferable "ground rules", remains elusive. It is neither a set of structural motifs nor intrinsic motions. Focusing on elastic network models, we here show that an allosteric lever -- a mode-coupling pattern induced by the perturbation -- governs the directional, source-to-target, allosteric communication: a structural perturbation of an allosteric site couples the excitation of localized hard elastic modes with concerted long range soft-mode relaxation. Perturbations of non-allosteric sites instead couple hard and soft modes uniformly. The allosteric response is shown to be generally non-linear and non-reciprocal, and allows for minimal structural distortions to be efficiently transmitted to specific changes at distant sites. Allosteric levers exist in proteins and "pseudoproteins" -- networks designed to display an allosteric response. Interestingly, protein sequences that constitute allosteric transmission channels are shown to be evolutionarily conserved. To illustrate how the results may be applied in drug design, we use them to successfully predict known allosteric sites in proteins.