迈向突变诱导的蛋白质结构变化的准确预测
Towards Accurate Prediction of Mutation-Induced Changes in Protein Structure
- Yale University（耶鲁大学）
机构由 AI 辅助整理，请以论文原文为准。
AI总结：
本研究基于PDB数据刻画突变诱导的蛋白质局部结构变化，评估AlphaFold3预测准确性随变形增大而下降，并发现溶剂可及性变化与变形相关性稳定，为预测单氨基酸突变结构变化提供框架。
AI中文摘要：
蛋白质相对于其野生型氨基酸序列可能拥有众多突变，而这些突变对其结构和功能的影响通常很小。然而，在其他情况下，即使相对于野生型序列的单个氨基酸突变也可能导致结构上的巨大变化，甚至引发疾病表型。尽管近年来野生型蛋白质结构预测的准确性已显著提高，但准确预测突变蛋白质的结构仍然困难。在此，我们针对来自蛋白质数据银行（PDB）的一组野生型及对应的单氨基酸突变体X射线晶体结构，刻画了蛋白质中局部突变诱导的结构变化。我们发现，这些蛋白质中突变诱导的结构变化局限于突变位点，并随着与突变位点空间距离的增加而迅速衰减。此外，我们评估了AlphaFold3在多大程度上能够重现X射线晶体结构中观察到的突变诱导的结构变形。我们发现，AlphaFold3预测的准确性随着突变诱导变形的增加而显著下降。与AlphaFold3的结果相反，单一物理特征（即溶剂可及性的变化）与突变诱导变形之间的皮尔逊相关性不依赖于变形的幅度。我们的结果和分析为旨在预测由单氨基酸突变引起的蛋白质结构变化的进一步研究提供了一个框架。
英文摘要：
Proteins can possess numerous mutations relative to their wild-type amino acid sequences with minimal impact to their structure and function. However, in other cases, even a single amino acid mutation relative to the wild-type sequence can lead to a large change in structure or even a disease phenotype. While the accuracy of wild-type protein structure prediction has improved significantly in recent years, it remains difficult to accurately predict the structure of mutant proteins. Here, we characterize the local mutation-induced structural changes in proteins for a dataset of wildtype and the corresponding single-amino acid mutant x-ray crystal structures from the Protein Data Bank (PDB). We find that mutation-induced structural changes in these proteins are localized at the site of the mutation, decaying rapidly with increasing spatial distance from the mutation site. In addition, we evaluate how well AlphaFold3 can recapitulate the observed mutation-induced structural deformations in the x-ray crystal structures. We find that the accuracy of the AlphaFold3 predictions decreases strongly with increasing mutation-induced deformation. In contrast to the results for AlphaFold3, the Pearson correlation between a single physical feature, i.e. the change in solvent accessibility, and the mutation-induced deformation does not depend on the magnitude of the deformation. Our results and analyses provide a framework for further studies aimed at predicting the structural changes in proteins caused by single amino acid mutations.
