Mutation effects of neuraminidases and their docking with ligands: a molecular dynamics and free energy calculation study
Mutation effects of neuraminidases and their docking with ligands: a molecular dynamics and free energy calculation study
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DOI：
10.1007/s10822-013-9691-1
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发表时间：
2013-11
影响因子：
3.5
通讯作者：
Zhiwei Yang;Gang Yang;Lijun Zhou
中科院分区：
文献类型：
--
作者：
Zhiwei Yang;Gang Yang;Lijun Zhou
对神经氨酸酶（NA）突变和NA抑制剂对接复合物进行了系统研究，目的是了解蛋白质-配体相互作用并设计具有最小抗性的广谱抗病毒药物。催化D151残基可能发生突变，而其他残基相对保守。NA活性位点构象通过突变而改变，但更多的改变不一定导致结合性质的更大偏差。已经讨论了所有相关突变的影响;例如，对于精氨酸三联体（R118、R292和R371），发现残基R118在配体结合过程中起最重要的作用。一般情况下，计算的结合自由能与实验观察吻合得很好。流感病毒对NA抑制剂的敏感性可以通过一些突变来加强;例如，通过E119 D突变，N2亚型配体的结合自由能从-18.0 kcalmol-1增加到-42.1 kcalmol-1。各种NA亚型的突变通常引起相似的构象和结合变化，解释了交叉耐药的发生;然而，在某些情况下可以检测到对应于亚型特异性耐药的差异。对于所有NA亚型，静电贡献是配体结合的主要驱动力，并且主要负责野生型和突变NA蛋白之间的结合差异。
A systematic study has been performed on neuraminidase (NA) mutations and NA-inhibitor docked complexes, with the aim to understand protein–ligand interactions and design broad-spectrum antiviral drugs with minimal resistances. The catalytic D151 residue is likely to mutate while others are relatively conserved. The NA active-site conformations are altered by mutations, but more alterations do not necessarily result in larger deviations to the binding properties. The effects of all related mutations have been discussed; e.g., for the arginine triad (R118, R292 and R371), it is found that residue R118 plays the most significant role during ligand binding. Generally, the calculated binding free energies agree well with the experimental observations. Susceptibility of influenza virus to NA inhibitors can be reinforced by some mutations; e.g., the binding free energies of ligands with N2 subtype increase from −18.0 to −42.1 kcal mol−1by the E119D mutation. Mutations of the various NA subtypes often cause similar conformational and binding changes, explaining the occurrence of cross resistances; nonetheless, differences can be detected in some cases that correspond to subtype-specific resistances. For all NA subtypes, the electrostatic contributions are the major driving force for ligand binding and largely responsible for the binding differences between the wild-type and mutated NA proteins.