Andrianov A M
Institute of Bioorganic Chemistry, Belarus Academy of Sciences, ac. Kuprevich St., 5/2, 220141 Minsk, Republic of Belarus.
J Biomol Struct Dyn. 2005 Dec;23(3):267-82. doi: 10.1080/07391102.2005.10507065.
The model describing the conformational properties of the HIV-1 principal neutralizing determinant in the geometric space of dihedrals was generated in terms of NMR spectroscopy data published in literature. To gain an object in view, the following successive steps were put into effect: (i) the NMR-based local structures for the HIV(MN) V3 loop were determined in water and in a mixed water/trifluoroethanol (TFE) solvent (7:3), (ii) in either case, the conformations of its irregular segments were analyzed and the secondary structure elements identified, (iii) to appreciate the degree of conformational mobility of the stretch of interest, the simulated structures were compared with each other, (iv) to detect the amino acids retaining their conformations inside the diverse HIV-1 isolates, the structures computed were collated with the one derived previously for the V3 loop from Thailand isolate, and (v) as a matter of record, the structurally rigid residues, that may present the forward-looking targets for AIDS drug researches, were revealed. Summing up the principal results arising from these studies, the following conclusions were drawn: I. The HIV(MN) V3 loop offers the highly mobile fragment of gp120 sensitive to its environment whose changes trigger the large-scale structural reforms, bringing in substantial altering the secondary structure of this functionally important site of the virus envelope. II. In water, it exhibits extended site 1-14 separated by double beta-turn 15-20 with unordered region 21-35. III. Adding the TFE gives rise to destruction of the regular structure in the V3 loop N-terminal, stimulates the formation of 3(10)-helix in site 24-31, and affects also its central region 20-25 forming the HIV-1 immunogenic crown. IV. Regardless of statistically significant differences between local structures of the HIV(MN) V3 loop in water and in water/TFE solution, over one-third of residues keeps their conformational states; the register of these amino acids comprises Asn-25 critical for virus binding with primary cell receptor CD4 as well as Arg-3 critical for utilization of CCR5 coreceptor. V. There are no conserved structural motifs within the V3 loops from Minnesota and Thailand HIV-1 strains. However, perceptible portion of amino acids (more than 35%), including those appearing in the functionally important regions of gp120, holds the values of dihedral angles in which case. The implications are discussed in conjunction with the data on the experimental observations for the HIV-1 principal neutralizing determinant.
根据文献中发表的核磁共振波谱数据，构建了一个描述HIV-1主要中和决定簇在二面角几何空间中构象性质的模型。为了达成目标，实施了以下连续步骤：（i）在水和水/三氟乙醇（TFE）混合溶剂（7:3）中确定基于核磁共振的HIV（MN）V3环局部结构；（ii）在任何一种情况下，分析其不规则片段的构象并识别二级结构元件；（iii）为了评估感兴趣片段的构象移动程度，将模拟结构相互比较；（iv）为了检测在不同HIV-1分离株中保持其构象的氨基酸，将计算得到的结构与先前从泰国分离株的V3环得到的结构进行比对；（v）作为记录，揭示了可能成为艾滋病药物研究前瞻性靶点的结构刚性残基。总结这些研究得出的主要结果，得出以下结论：I. HIV（MN）V3环提供了gp120的高度可移动片段，对其环境敏感，环境变化会引发大规模结构改革，从而显著改变病毒包膜这一功能重要位点的二级结构。II. 在水中，它呈现出由双β-转角15-20分隔的延伸位点1-14，以及无序区域21-35。III. 添加TFE会导致V3环N端规则结构的破坏，刺激位点24-31中3（10）-螺旋的形成，并且还会影响其形成HIV-1免疫原性冠的中心区域20-25。IV. 无论HIV（MN）V3环在水和水/TFE溶液中的局部结构存在统计学上的显著差异，超过三分之一的残基保持其构象状态；这些氨基酸包括对病毒与初级细胞受体CD4结合至关重要的Asn-25以及对CCR5共受体利用至关重要的Arg-3。V. 来自明尼苏达和泰国HIV-1菌株的V3环内不存在保守的结构基序。然而，相当一部分氨基酸（超过35%），包括那些出现在gp120功能重要区域的氨基酸，在这种情况下保持二面角的值。结合关于HIV-1主要中和决定簇的实验观察数据对这些影响进行了讨论。
