QresFEP: An Automated Protocol for Free Energy Calculations of Protein Mutations in Q
QresFEP: An Automated Protocol for Free Energy Calculations of Protein Mutations in Q
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DOI：
10.1021/acs.jctc.9b00538
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发表时间：
2019-10-01
影响因子：
5.5
通讯作者：
Gutierrez-de-Teran, Hugo
中科院分区：
文献类型：
--
作者：
Jespers, Willem;Isaksen, Geir V.;Gutierrez-de-Teran, Hugo
预测单点突变对蛋白质稳定性或蛋白质与配体结合的影响是计算生物学中的一个主要挑战。自由能计算构成了解决这个问题的最严格的方法，尽管氨基酸突变的收敛值的估计仍然具有挑战性。为了克服这一限制，我们开发了量身定制的协议来计算与单点突变相关的自由能移位。在这里，我们描述了QresFEP协议，它包括我们最近的协议的扩展，以涵盖所有氨基酸突变，基于最新版本的OPLS-AA力场。QresFEP是在应用程序编程接口框架和图形界面QGui中实现的，对于分子动力学软件Q，完整的协议在几个模型系统中进行了基准测试，优化了一些采样参数，并实现了兹万齐格指数公式和Bennet的接受率方法。QresFEP在估算氨基酸侧链模拟物，包括它们的带电类似物的水合自由能方面表现出很好的性能。我们还考察了它在药物相关的蛋白质-配体结合问题上的表现，神经肽Y，G蛋白偶联受体的拮抗作用。在这里，计算结果与16个突变对拮抗剂BIBP3226结合的实验结果显示出非常好的一致性，与我们最近在这一领域的应用相一致。最后，对43个T4-溶菌酶突变的表征揭示了我们的方案能够评估蛋白质热稳定性的变化，实现了与替代自由能扰动(FEP)方法类似的性能。总之，QresFEP是一种健壮、通用和用户友好的计算型FEP协议，可以高精度地检测单点突变的生化效应。
Predicting the effect of single-point mutations on protein stability or protein-ligand binding is a major challenge in computational biology. Free energy calculations constitute the most rigorous approach to this problem, though the estimation of converged values for amino acid mutations remains challenging. To overcome this limitation, we developed tailored protocols to calculate free energy shifts associated with single-point mutations. We herein describe the QresFEP protocol, which includes an extension of our recent protocols to cover all amino acids mutations, based on the latest versions of the OPLS-AA force field. QresFEP is implemented in an application programming interface framework and the graphic interface QGui, for the molecular dynamics software Q The complete protocol is benchmarked in several model systems, optimizing a number of sampling parameters and the implementation of Zwanzig's exponential formula and Bennet's acceptance ratio methods. QresFEP shows an excellent performance on estimating the hydration free energies of amino acid side-chain mimics, including their charged analogues. We also examined its performance on a protein-ligand binding problem of pharmaceutical relevance, the antagonism of neuropeptide Y, G protein-coupled receptor. Here, the calculations show very good agreement with the experimental effect of 16 mutations on the binding of antagonists BIBP3226, in line with our recent applications in this field. Finally, the characterization of 43 mutations of T4-lysozyme reveals the capacity of our protocol to assess variations of the thermal stability of proteins, achieving a similar performance to alternative free energy perturbation (FEP) approaches. In summary, QresFEP is a robust, versatile, and user-friendly computational FEP protocol to examine biochemical effects of single-point mutations with high accuracy.