Zhao Mingfei, Lopes Laura J S, Sahni Harshita, Yadav Anju, Do Hung N, Reddy Tyler, López Cesar A, Neale Chris, Gnanakaran S
T-6 Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico 87545, United States.
Department of Computer Science, University of New Mexico, Albuquerque, New Mexico 87106,United States.
J Phys Chem B. 2024 Dec 26;128(51):12710-12727. doi: 10.1021/acs.jpcb.4c05018. Epub 2024 Dec 13.
A fundamental understanding of how the HIV-1 envelope (Env) protein facilitates fusion is still lacking. The HIV-1 fusion peptide, consisting of 15 to 22 residues, is the N-terminus of the gp41 subunit of the Env protein. Further, this peptide, a promising vaccine candidate, initiates viral entry into target cells by inserting and anchoring into human immune cells. The influence of membrane lipid reorganization and the conformational changes of the fusion peptide during the membrane insertion and anchoring processes, which can significantly affect HIV-1 cell entry, remains largely unexplored due to the limitations of experimental measurements. In this work, we investigate the insertion of the fusion peptide into an immune cell membrane mimic through multiscale molecular dynamics simulations. We mimic the native T-cell by constructing a nine-lipid asymmetric membrane, along with geometrical restraints accounting for insertion in the context of gp41. To account for the slow time scale of lipid mixing while enabling conformational changes, we implement a protocol to go back and forth between atomistic and coarse-grained simulations. Our study provides a molecular understanding of the interactions between the HIV-1 fusion peptide and the T-cell membrane, highlighting the importance of the conformational flexibility of fusion peptides and local lipid reorganization in stabilizing the anchoring of gp41 into the targeted host membrane during the early events of HIV-1 cell entry. Importantly, we identify a motif within the fusion peptide critical for fusion that can be further manipulated in future immunological studies.
目前仍缺乏对HIV-1包膜（Env）蛋白如何促进融合的基本理解。HIV-1融合肽由15至22个残基组成，是Env蛋白gp41亚基的N端。此外，这种肽作为一种有前景的疫苗候选物，通过插入并锚定到人类免疫细胞中来启动病毒进入靶细胞。由于实验测量的局限性，在膜插入和锚定过程中膜脂重排以及融合肽构象变化的影响（这可能会显著影响HIV-1细胞进入）在很大程度上仍未得到探索。在这项工作中，我们通过多尺度分子动力学模拟研究了融合肽插入免疫细胞膜模拟物的过程。我们通过构建一个九脂质不对称膜来模拟天然T细胞，并结合几何约束来考虑在gp41背景下的插入情况。为了在考虑脂质混合缓慢时间尺度的同时允许构象变化，我们实施了一种在原子尺度和粗粒度模拟之间来回切换的方案。我们的研究提供了对HIV-1融合肽与T细胞膜之间相互作用的分子理解，突出了融合肽构象灵活性和局部脂质重排在HIV-1细胞进入早期事件中稳定gp41锚定到靶向宿主膜中的重要性。重要的是，我们在融合肽中确定了一个对融合至关重要的基序，可在未来的免疫学研究中进一步加以操控。
