Department of Chemical and Biological Engineering, Drexel University, Philadelphia, PA, USA.
Biophys J. 2010 Nov 17;99(10):3438-44. doi: 10.1016/j.bpj.2010.09.054.
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 α-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.
HIV-1 糖蛋白 gp41 的 27 残基跨膜结构域（MSD）具有对病毒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，基于结构的这些和其他 MSD 特征的作用解释仍然不清楚。我们使用全原子、显式溶剂和膜锚定模型的分子动力学和元动力学计算来研究 HIV-1 gp41 MSD 的构象可变性。我们发现 MSD 肽在膜中呈稳定倾斜的α-螺旋构象。然而，当中间跨距 Arg（694）的侧链“潜水”到病毒膜的外叶时，MSD 会呈现出一种亚稳态构象，其中高度保守的 N 端核心（位于 Lys（681）和 Arg（694）之间，包含 GXXXG 基序）展开。相比之下，当 Arg（694）的侧链潜水到内叶时，MSD 肽呈现出与实验观察一致的亚稳态构象，其中肽在 Phe（697）处弯曲，以促进 Arg（694）潜水。这两种模型都表明 gp41 可能以特定方式破坏病毒膜，为病毒与靶细胞融合做好准备。
