T‐20 and T‐1249 HIV fusion inhibitors' structure and conformation in solution: a molecular dynamics study
T‐20 and T‐1249 HIV fusion inhibitors' structure and conformation in solution: a molecular dynamics study
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T-20 和 T-1249 HIV 融合抑制剂在溶液中的结构和构象：分子动力学研究
作者：
A. M. D. Canto;A. J. P. Carvalho;J. Ramalho;L. Loura;L. Loura
HIV包膜与靶细胞膜的融合是HIV进入靶细胞的关键步骤。基于HIV gp 41的C区的几种肽已在临床试验中用作可能的HIV融合抑制剂。其中包括T-1249和T-20（也称为恩呋维肽）。尽管最近的工作，这些分子的抑制机制的详细分子图片仍然缺乏。这些肽通常通过与它们同源的gp 41蛋白序列的结构类比而被描述为α-螺旋。然而，像这样的结构在溶液中是高度不稳定的，因此它们本身不能解释这两种融合抑制剂必须被水溶剂化并与细胞膜有效相互作用的能力。为此，进行了广泛的分子动力学模拟，以研究T-1249和T-20在水中的结构和构象行为，以及较短的同源肽CTP和3f 5，它们没有显示出抑制作用。我们发现，所研究的抑制剂在溶液中没有稳定的结构在所研究的时间尺度。此外，溶剂可及区域在模拟期间显著变化。我们的研究结果表明，这些肽在溶液中可能不仅具有一种，而且具有几种可能的结构，其中一些更适合与溶剂相互作用，而另一些可能更适合与细胞膜相互作用。有趣的是，根据已发表的实验研究，我们证实T-1249显示出比T-20大得多的α螺旋结构。考虑到最近的一项关于设计具有增加的螺旋度的肽的研究，该特征可能与T-1249相对于T-20的抑制效率增加有关。版权所有© 2007年欧洲肽协会和约翰威利父子有限公司。
Fusion of the HIV envelope with the target cell membrane is a critical step of the HIV entry into the target cell. Several peptides based on the C‐region of HIV gp41 have been used in clinical trials as possible HIV fusion inhibitors. Among these are T‐1249 and T‐20 (also known as enfurvitide). Despite recent works, a detailed molecular picture of the inhibitory mechanism of these molecules is still lacking. These peptides are usually depicted as α‐helices by analogy with the structure of the sequence of the gp41 protein with which they are homologous. However, structures like these would be highly unstable in solution and thus would not explain, by themselves, the ability that the two fusion inhibitors have to become solvated by water and also interact effectively with cell membranes. To this effect, extensive molecular dynamics simulations were carried out to investigate the structure and conformational behavior of T‐1249 and T‐20 in water, as well as shorter homologous peptides CTP and 3f5, which show no inhibitory action. We found that the studied inhibitors have no stable structure in solution in the time scale studied. Additionally, the solvent accessible area varies significantly during the simulation. Our findings suggest that these peptides may assume not only one, but several possible sets of structures in solution, some of which more adequate to interact with the solvent, whereas others might be better suited to interact with cell membranes. Interestingly, and in accordance with published experimental studies, we verified that T‐1249 displays considerably larger α‐helical structure than T‐20. Taking into account a recent study with design peptides with increased helicity, it is possible that this feature may be related to the increased inhibiting efficiency of T‐1249 relative to that of T‐20. Copyright © 2007 European Peptide Society and John Wiley & Sons, Ltd.