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Allosteric Lever: Toward a Principle of Specific Allosteric Response

Maximilian Vossel1, Bert L. de Groot2, and Aljaž Godec1,*

  • *Contact author: agodec@mpinat.mpg.de
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Phys. Rev. X 15, 021097 – Published 20 June, 2025

DOI: https://doi.org/10.1103/wv2k-676p

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 nonallosteric sites instead couple hard and soft modes uniformly. The allosteric response is shown to be generally nonlinear and nonreciprocal, 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.

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Popular Summary

Allostery is the process by which a change at one site of a molecule—such as ligand binding—affects activity at a distant site, enabling control over the function of proteins and nucleic acids. Despite its central role in biology, the physical basis of allostery has remained unclear. It cannot be fully explained by recurring structural motifs, simple dynamic behaviors, or thermodynamic principles alone. Instead, it seems to require complex, coordinated motion that depends sensitively on a molecule’s structure. In this study, we identify a specific mechanism—an “allosteric lever”—that explains how structural changes are transmitted across proteins.

We investigate this mechanism using elastic network models of proteins and develop a method to analyze how these structures respond nonlinearly to mechanical perturbations. We find that in proteins with allosteric activity, perturbations at key sites induce a specific coupling between stiff, localized motions and broader, softer deformations. In contrast, perturbations at nonallosteric sites lead to more uniform and less directed responses. This coupling mechanism explains how minimal changes at one site can lead to specific functional effects at distant locations. We also find that the amino-acid sequences responsible for this transmission tend to be evolutionarily conserved.

Our findings show that allostery is an inherent property of protein structures that is selectively amplified in certain cases. The response is nonlinear and directional, requiring an actual perturbation to be observed, making it a fundamentally nonequilibrium phenomenon. This insight could help guide the design of new biomolecules with tunable allosteric properties, with potential applications in drug design and synthetic biology.

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Phys. Rev. X 15, 021097– Published 20 June, 2025
  • Received 13 November 2023
  • Accepted 15 May 2025
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