All-Atom Models of the Membrane-Spanning Domain of HIV-1 gp41 from Metadynamics
All-Atom Models of the Membrane-Spanning Domain of HIV-1 gp41 from Metadynamics
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DOI：
10.1016/j.bpj.2010.09.054
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发表时间：
2010-11-17
影响因子：
3.4
通讯作者：
Abrams, Cameron F.
中科院分区：
文献类型：
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作者：
Gangupomu, Vamshi K.;Abrams, Cameron F.
HIV-1糖蛋白gp 41的27个残基的跨膜结构域（MSD）具有对病毒的生物学功能至关重要的保守序列元件，特别是保守的GXXXG基序和中跨精氨酸。然而，对这些和其他MSD特征的作用的基于结构的解释仍然不清楚。使用分子动力学和metadhesics计算的全原子，明确的溶剂，和膜锚定模型，我们研究了HIV-1 gp 41 MSD的构象变异性。我们发现MSD肽在膜中呈现稳定的倾斜α-螺旋构象。然而，当中跨Arg（694）的侧链“潜入”到病毒膜的外小叶时，MSD呈现亚稳态构象，其中高度保守的N-末端核心（在Lys（681）和Arg（694）之间并包含GXXXG基序）展开。相比之下，当Arg（694）侧链潜入内小叶时，MSD肽呈现亚稳态构象，与实验观察结果一致，其中肽在Phe（697）处扭结以促进Arg（694）潜入。这两种模型都表明了gp 41可能使病毒膜不稳定的特定方式，从而引发病毒与靶细胞融合。
The 27-residue membrane-spanning domain (MSD) of the HIV-1 glycoprotein gp41 bears conserved sequence elements crucial to the biological function of the virus, in particular a conserved GXXXG motif and a midspan arginine. However, structure-based explanations for the roles of these and other MSD features remain unclear. Using molecular dynamics and metadynamics calculations of an all-atom, explicit solvent, and membrane-anchored model, we study the conformational variability of the HIV-1 gp41 MSD. We find that the MSD peptide assumes a stable tilted alpha-helical conformation in the membrane. However, when the side chain of the midspan Arg(694) "snorkels" to the outer leaflet of the viral membrane, the MSD assumes a metastable conformation where the highly-conserved N-terminal core (between Lys(681) and Arg(694) and containing the GXXXG motif) unfolds. In contrast, when the Arg(694) side chain snorkels to the inner leaflet, the MSD peptide assumes a metastable conformation consistent with experimental observations where the peptide kinks at Phe(697) to facilitate Arg(694) snorkeling. Both of these models suggest specific ways that gp41 may destabilize viral membrane, priming the virus for fusion with a target cell.