Computational Alanine Scanning Mutagenesis: MM-PBSA vs TI

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• 作者：S铆lvia A. Martins ; Marta A. S. Perez ; Irina S. Moreira ; S茅rgio F. Sousa ; M. J. Ramos ; P. A. Fernandes
• 刊名：Journal of Chemical Theory and Computation
• 出版年：2013
• 出版时间：March 12, 2013
• 年：2013
• 卷：9
• 期：3
• 页码：1311-1319
• 全文大小：279K
• 年卷期：v.9,no.3(March 12, 2013)
• ISSN：1549-9626

文摘

Understanding protein鈥損rotein association and being able to determine the crucial residues responsible for their association (hot-spots) is a key issue with huge practical applications such as rational drug design and protein engineering. A variety of computational methods exist to detect hot-spots residues, but the development of a fast and accurate quantitative alanine scanning mutagenesis (ASM) continues to be crucial. Using four protein鈥損rotein complexes, we have compared a variation of the standard computational ASM protocol developed at our group, based on the Molecular Mechanics/Poisson鈥揃oltzmann Surface Area (MM-PBSA) approach, against Thermodynamic Integration (TI), a well-known and accurate but computationally expensive method. To compare the efficiency and the accuracy of the two methods, we have calculated the protein鈥損rotein binding free energy differences upon alanine mutation of interfacial residues (螖螖G_bind). In relation to the experimental 螖螖G_bind values, the average error obtained with TI was 1.53 kcal/mol, while the ASM protocol resulted in an average error of 1.18 kcal/mol. The results demonstrate that the much faster ASM protocol gives results at the same level of accuracy as the TI method but at a fraction of the computational time required to run TI. This ASM protocol is therefore a strong and efficient alternative to the systematic evaluation of protein鈥損rotein interfaces, involving hundreds of amino acid residues in search of hot-spots.