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

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.

@article{frellsen2025_2506.05596,
  title={ Zero-shot protein stability prediction by inverse folding models: a free energy interpretation },
  author={ Jes Frellsen and Maher M. Kassem and Tone Bengtsen and Lars Olsen and Kresten Lindorff-Larsen and Jesper Ferkinghoff-Borg and Wouter Boomsma },
  journal={arXiv preprint arXiv:2506.05596},
  year={ 2025 }
}