Department of Structural Biology , Weizmann Institute of Science , Rehovot 76100 , Israel.
J Phys Chem B. 2018 Dec 13;122(49):11450-11459. doi: 10.1021/acs.jpcb.8b07379. Epub 2018 Sep 25.
Predicting the effect of a single point mutation on protein thermodynamic stability (ΔΔ G) is an ongoing challenge with high relevance for both fundamental and applicable aspects of protein science. Drawbacks that limit the predictive power of stability prediction tools include the lack of representations for the explicit energetic terms of the unfolded state. Using coarse-grained simulations and analytical modeling analysis, we found that a mutation that involves the breaking of long-range contacts may lead to an increase in the unfolded state entropy, which can lead to an overall destabilization of the protein. A bioinformatics analysis indicates that the effect of mutation on the unfolded state is greater for hydrophobic or charged (compared with polar) residues that participate in long-range contacts through a loop length longer than 18 amino acids and whose formation probabilities are relatively high.
预测单点突变对蛋白质热力学稳定性（ΔΔG）的影响是一个具有重要意义的挑战，既涉及蛋白质科学的基础研究，也涉及应用研究。限制稳定性预测工具预测能力的缺点包括缺乏对展开状态的明确能量项的表示。通过粗粒化模拟和分析建模分析，我们发现涉及长程接触破坏的突变可能导致展开状态熵的增加，从而导致蛋白质的整体不稳定。生物信息学分析表明，对于通过长度超过 18 个氨基酸的环参与长程接触的疏水性或带电（与极性相比）残基，以及其形成概率相对较高的残基，突变对展开状态的影响更大。
