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  • Open Access

Out-of-Equilibrium Selection Pressure Enhances Inference from Protein Sequence Data

Nicola Dietler, Cyril Malbranke, and Anne-Florence Bitbol*

  • *Contact author: anne-florence.bitbol@epfl.ch
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Phys. Rev. Lett. 136, 108402 – Published 11 March, 2026

DOI: https://doi.org/10.1103/1ht9-njrr

Abstract

Homologous proteins have similar three-dimensional structures and biological functions that shape their sequences. The resulting coevolution-driven correlations underlie methods from Potts models to alphafold, which infer protein structure and function from sequences. Using a minimal model, we show that fluctuating selection strength and the onset of new selection pressures improve coevolution-based inference of structural contacts. Our conclusions extend to realistic synthetic data and to the inference of interaction partners. Out-of-equilibrium noise arising from ubiquitous variations in natural selection thus enhances, rather than hinders, the success of inference from protein sequences.

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Phys. Rev. Lett. 136, 108402– Published 11 March, 2026
  • Received 14 May 2025
  • Revised 20 December 2025
  • Accepted 11 February 2026
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Published by the American Physical Society under the terms of the Creative Commons Attribution 4.0 International license. Further distribution of this work must maintain attribution to the author(s) and the published article’s title, journal citation, and DOI.

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