Zero-shot protein stability prediction by inverse folding models: a free energy interpretation

• URL: http://arxiv.org/abs/2506.05596v1
• Date: Thu, 05 Jun 2025 21:15:13 GMT
• Title: Zero-shot protein stability prediction by inverse folding models: a free energy interpretation
• Authors: Jes Frellsen, Maher M. Kassem, Tone Bengtsen, Lars Olsen, Kresten Lindorff-Larsen, Jesper Ferkinghoff-Borg, Wouter Boomsma,
• Abstract summary: Inverse folding models have proven to be highly effective zero-shot predictors of protein stability.<n>We take steps to clarify the free-energy foundations of inverse folding models.
• Score: 6.481107286523549
• License: http://arxiv.org/licenses/nonexclusive-distrib/1.0/
• Abstract: Inverse folding models have proven to be highly effective zero-shot predictors of protein stability. Despite this success, the link between the amino acid preferences of an inverse folding model and the free-energy considerations underlying thermodynamic stability remains incompletely understood. A better understanding would be of interest not only from a theoretical perspective, but also potentially provide the basis for stronger zero-shot stability prediction. In this paper, we take steps to clarify the free-energy foundations of inverse folding models. Our derivation reveals the standard practice of likelihood ratios as a simplistic approximation and suggests several paths towards better estimates of the relative stability. We empirically assess these approaches and demonstrate that considerable gains in zero-shot performance can be achieved with fairly simple means.

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