Georgoulia Panagiota S, Glykos Nicholas M
Department of Molecular Biology and Genetics, Democritus University of Thrace, University Campus, Alexandroupolis 68100, Greece.
ACS Omega. 2018 Nov 2;3(11):14746-14754. doi: 10.1021/acsomega.8b01579. eCollection 2018 Nov 30.
T-20 peptide is the first FDA-approved fusion inhibitor against AIDS/HIV-1 gp41 protein. Part of it, the gp41[659-671] peptide, that contains the complete epitope for the neutralizing 2F5 monoclonal antibody, has been found experimentally in a number of divergent structures. Herein, we attempt to reconcile them by using unbiased large-scale all-atom molecular dynamics folding simulations. We show that our approach can successfully capture the peptide's heterogeneity and reach each and every experimentally determined conformation in sub-angstrom accuracy, whilst preserving the peptide's disordered nature. Our analysis also unveils that the minor refinements within the AMBER99SB family of force fields can lead to appreciable differences in the predicted conformational stability arising from subtle differences in the helical- and β-region of the Ramachandran plot. Our work underlines the contribution of molecular dynamics simulation in structurally characterizing pharmacologically important peptides of ambiguous structure.
T-20肽是首个获得美国食品药品监督管理局（FDA）批准的针对艾滋病病毒/1型人类免疫缺陷病毒（AIDS/HIV-1）gp41蛋白的融合抑制剂。其中一部分，即gp41[659-671]肽，包含针对中和性2F5单克隆抗体的完整表位，已在实验中发现具有多种不同结构。在此，我们尝试通过使用无偏大规模全原子分子动力学折叠模拟来协调这些结构。我们表明，我们的方法能够成功捕捉该肽的异质性，并以亚埃精度达到每个实验确定的构象，同时保留该肽的无序性质。我们的分析还揭示，AMBER99SB力场家族中的微小改进可能会因拉马钱德兰图的螺旋区和β区的细微差异而导致预测的构象稳定性出现显著差异。我们的工作强调了分子动力学模拟在对结构模糊的药理学重要肽进行结构表征方面的作用。
