用自由能视角重新解释逆折叠模型，提升蛋白质稳定性预测能力
Zero-shot protein stability prediction by inverse folding models: a free energy interpretation
- 将逆折叠模型的氨基酸偏好与自由能关联，揭示其理论基础
- 发现传统似然比是简化近似，提出更优的稳定性估计方法
- 仅用简单改进，零样本预测性能显著提升，适合结构生物学研究者
逆折叠模型已被证明是高效的零样本蛋白质稳定性预测工具。尽管取得了成功，但逆折叠模型中氨基酸偏好与热力学稳定性的自由能机制之间的联系仍不完全清楚。深入理解这一关系不仅具有理论意义，还可能为更强的零样本稳定性预测提供基础。本文致力于阐明逆折叠模型的自由能基础。我们的推导表明，标准的似然比方法是一种简化的近似，同时提出了几种更优的相对稳定性估计路径。我们通过实验评估了这些方法，结果表明，仅通过较简单的手段即可实现零样本性能的显著提升。
原文摘要 · Abstract (English)
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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