Ramírez-Salinas Gema L, García-Machorro J, Quiliano Miguel, Zimic Mirko, Briz Verónica, Rojas-Hernández Saul, Correa-Basurto J
Laboratorio de Modelado Molecular y Bioinformática, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, 11340, México City, Mexico.
Laboratorio de Medicina de Conservación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, Mexico, DF, 11340, México.
J Mol Model. 2015 Nov;21(11):292. doi: 10.1007/s00894-015-2835-6. Epub 2015 Oct 26.
The goal of this study was to identify neuraminidase (NA) residue mutants from human influenza AH1N1 using sequences from 1918 to 2012. Multiple alignment studies of complete NA sequences (5732) were performed. Subsequently, the crystallographic structure of the 1918 influenza (PDB ID: 3BEQ-A) was used as a wild-type structure and three-dimensional (3-D) template for homology modeling of the mutated selected NA sequences. The 3-D mutated NAs were refined using molecular dynamics (MD) simulations (50 ns). The refined 3-D models were used to perform docking studies using oseltamivir. Multiple sequence alignment studies showed seven representative mutations (A232V, K262R, V263I, T264V, S367L, S369N, and S369K). MD simulations applied to 3-D NAs showed that each NA had different active-site shapes according to structural surface visualization and docking results. Moreover, Cartesian principal component analyses (cPCA) show structural differences among these NA structures caused by mutations. These theoretical results suggest that the selected mutations that are located outside of the active site of NA could affect oseltamivir recognition and could be associated with resistance to oseltamivir.
本研究的目的是利用1918年至2012年的序列，从人类甲型H1N1流感中鉴定神经氨酸酶（NA）残基突变体。对完整的NA序列（5732条）进行了多序列比对研究。随后，将1918年流感病毒的晶体结构（PDB ID：3BEQ - A）用作野生型结构和三维（3 - D）模板，对选定的突变NA序列进行同源建模。使用分子动力学（MD）模拟（50纳秒）对3 - D突变的NA进行优化。使用奥司他韦对优化后的3 - D模型进行对接研究。多序列比对研究显示了七个代表性突变（A232V、K262R、V263I、T264V、S367L、S369N和S369K）。应用于3 - D NA的MD模拟表明，根据结构表面可视化和对接结果，每个NA具有不同的活性位点形状。此外，笛卡尔主成分分析（cPCA）显示这些NA结构之间因突变而存在结构差异。这些理论结果表明，位于NA活性位点之外的选定突变可能会影响奥司他韦识别，并可能与对奥司他韦的耐药性有关。
