Molecular Insight into the Interaction between IFABP and PA by Using MM-PBSA and Alanine Scanning Methods

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• 作者：Hanjun Zou ; Cheng Luo ; Suxin Zheng ; Xiaomin Luo ; Weiliang Zhu ; Kaixian Chen ; Jianhua Shen ; Hualiang Jiang
• 刊名：Journal of Physical Chemistry B
• 出版年：2007
• 出版时间：August 2, 2007
• 年：2007
• 卷：111
• 期：30
• 页码：9104 - 9113
• 全文大小：383K
• 年卷期：v.111,no.30(August 2, 2007)
• ISSN：1520-5207

文摘

The molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method combined with alanine-scanning mutagenesis is a very important tool for rational drug design. In this study, molecular dynamics(MD) and MM-PBSA were applied to calculate the binding free energy between the rat intestinal fatty acidbinding protein (IFABP) and palmitic acid (PA) to gain insight to the interaction details. Equally spacedsnapshots along the trajectory were chosen to perform the binding free energy calculation, which yields aresult highly consistent with experimental value with a deviation of 0.4 kcal/mol. Computational alaninescanning was performed on the same set of snapshots by mutating the residues in IFABP to alanine andrecomputing the G_binding. By postprocessing a single trajectory of the wild-type complex, the averageunsigned error of our calculated G_binding is below 1.5 kcal/mol for most of the alanine mutations of thenoncharged residues (67% in total). To further investigate some particular mutants, three additional dynamicalsimulations of IFABP Arg126Ala, Arg106Ala, and Arg106Gln mutants were conducted. Recalculated bindingfree energies are well consistent with the experimental data. Moreover, the ambiguous role of Arg106 causedby the free energy change of the opposite sign when it is mutated to alanine and glutamine respectively isclarified both structurally and energetically. Typically, this can be attributed to the partial electrostaticcompensation mainly from Arg56 and the obvious entropy gain in Arg106Ala mutant while not in Arg106Glnmutant. The presented structural model of IFABP-PA complex could be used to guide future studies.