Andrianov A M
Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Kuprevich Street 5/2, 220141 Minsk, Republic of Belarus.
J Biomol Struct Dyn. 2008 Aug;26(1):49-56. doi: 10.1080/07391102.2008.10507222.
The object of the study was to model the structural complex of the FK506-binding protein (FKBP) with the CRK peptide imitating the central region of the HIV-1 V3 loop, as well as to define the FKBP stretch giving rise to the binding site for V3 the synthetic copy of which, on the assumption of preserving the spatial peptide structure in the free state, can be considered as a promising applicant for the role of antiviral drug. To this end, the following successive steps were carried out: (i) the NMR-based conformational analysis of CRK was put into practice, and, in the light of the results derived, the best energy CRK structure meeting the requirements of the input NMR data was identified; (ii) molecular docking of the CRK structure with the X-ray FKBP conformation was implemented, and energy refining the simulated structural complex was realized; (iii) the matrix of distances between amino acids of the ligand and receptor was computed to specify the FKBP stretch keeping in touch with CRK followed by analyzing the types of interactions stabilizing the over-molecular ensemble; (iv) 3D structure of this stretch in the unbound status referred to as the FKBP peptide was predicted, and its collation with the X-ray conformation of the identical FKBP site was performed; (v) the potential energy function and its constituents were studied for the structural complex generated by molecular docking of the CRK molecule with the FKBP peptide; and (vi) from all evidence, the virtual FKBP-derived peptide was submitted to be utilized as a prospective structural framework in the anti-HIV-1 drug design. Summing up the results obtained, the following principal conclusion was drawn: a high affinity of the V3 loop peptide to the FKBP is based on the principle of "mirror similarity" that implies the near resemblance of 3D structures for the two individual fragments of the receptor and ligand, which, most likely, accounts for recognizing the immunophilin by V3 and determines the specificity of their efficacious interactions arising from the experimental observations.
本研究的目的是对FK506结合蛋白（FKBP）与模仿HIV-1 V3环中心区域的CRK肽的结构复合物进行建模，以及确定产生V3结合位点的FKBP片段。假定该片段的合成拷贝在自由状态下保留空间肽结构，则可将其视为抗病毒药物角色的有前景的候选物。为此，进行了以下连续步骤：（i）对CRK进行基于核磁共振的构象分析，并根据所得结果确定符合输入核磁共振数据要求的最佳能量CRK结构；（ii）将CRK结构与X射线FKBP构象进行分子对接，并对模拟的结构复合物进行能量优化；（iii）计算配体和受体氨基酸之间的距离矩阵，以确定与CRK接触的FKBP片段，随后分析稳定超分子整体的相互作用类型；（iv）预测该片段在未结合状态下的3D结构，即FKBP肽，并将其与相同FKBP位点的X射线构象进行比对；（v）研究CRK分子与FKBP肽分子对接产生的结构复合物的势能函数及其组成部分；（vi）根据所有证据，提交虚拟的源自FKBP的肽，以用作抗HIV-1药物设计中的潜在结构框架。总结所得结果，得出以下主要结论：V3环肽与FKBP的高亲和力基于“镜像相似性”原理，这意味着受体和配体的两个单独片段的3D结构近乎相似，这很可能解释了V3对亲免素的识别，并决定了从实验观察中产生的有效相互作用的特异性。
