Brown Benjamin P, Stein Richard A, Meiler Jens, Mchaourab Hassane
Department of Chemistry, Vanderbilt University, Nashville, TN, USA. Nashville, TN 37232, USA.
Center for Structural Biology, Vanderbilt University, Nashville, TN, USA. Nashville, TN 37232, USA.
bioRxiv. 2023 Aug 7:2023.08.06.552168. doi: 10.1101/2023.08.06.552168.
Protein dynamics are intimately tied to biological function and can enable processes such as signal transduction, enzyme catalysis, and molecular recognition. The relative free energies of conformations that contribute to these functional equilibria are evolved for the physiology of the organism. Despite the importance of these equilibria for understanding biological function and developing treatments for disease, the computational and experimental methods capable of quantifying them are limited to systems of modest size. Here, we demonstrate that AlphaFold2 contact distance distributions can approximate conformational Boltzmann distributions, which we evaluate through examination of the joint probability distributions of inter-residue contact distances along functionally relevant collective variables of several protein systems. Further, we show that contact distance probability distributions generated by AlphaFold2 are sensitive to points mutations thus AF2 can predict the structural effects of mutations in some systems. We anticipate that our approach will be a valuable tool to model the thermodynamics of conformational changes in large biomolecular systems.
蛋白质动力学与生物功能密切相关，并能促成信号转导、酶催化和分子识别等过程。有助于这些功能平衡的构象的相对自由能是为生物体的生理机能而演化的。尽管这些平衡对于理解生物功能和开发疾病治疗方法很重要，但能够对其进行量化的计算和实验方法仅限于中等规模的系统。在这里，我们证明了AlphaFold2接触距离分布可以近似构象玻尔兹曼分布，我们通过检查沿着几个蛋白质系统的功能相关集体变量的残基间接触距离的联合概率分布来评估这一点。此外，我们表明由AlphaFold2生成的接触距离概率分布对单点突变敏感，因此AF2可以预测某些系统中突变的结构效应。我们预计我们的方法将成为模拟大型生物分子系统构象变化热力学的有价值工具。
