Kamath Shantaram, Wong Tuck C
Department of Chemistry, University of Missouri, Columbia, Missouri 65211, USA.
Biophys J. 2002 Jul;83(1):135-43. doi: 10.1016/S0006-3495(02)75155-2.
The structures of the 16-residue fusion domain (or fusion peptide, FP) of the human immunodeficiency virus gp41 fusion protein, two of its mutants, and a shortened peptide (5-16) were studied by molecular dynamics simulation in an explicit palmitoyloleoylphosphoethanolamine bilayer. The simulations showed that the active wild-type FP inserts into the bilayer approximately 44 degrees +/- 6 degrees with respect to the bilayer normal, whereas the inactive V2E and L9R mutants and the inactive 5 to 16 fragment lie on the bilayer surface. This is the first demonstration by explicit molecular dynamics of the oblique insertion of the fusion domain into lipid bilayers, and provides correlation between the mode of insertion and the fusogenic activity of these peptides. The membrane structure of the wild-type FP is remarkably similar to that of the influenza HA(2) FP as determined by nuclear magnetic resonance and electron spin resistance power saturation. The secondary structures of the wild-type FP and the two inactive mutants are quite similar, indicating that the secondary structure of this fusion domain plays little or no role in affecting the fusogenic activity of the fusion peptide. The insertion of the wild-type FP increases the thickness of the interfacial area of the bilayer by disrupting the hydrocarbon chains and extending the interfacial area toward the head group region, an effect that was not observed in the inactive FPs.
在明确的棕榈油酰油酰磷脂酰乙醇胺双层膜中，通过分子动力学模拟研究了人类免疫缺陷病毒gp41融合蛋白的16个残基融合结构域（或融合肽，FP）、其两个突变体以及一个缩短肽（5 - 16）的结构。模拟结果表明，活性野生型FP相对于双层膜法线以约44度±6度的角度插入双层膜中，而无活性的V2E和L9R突变体以及无活性的5至16片段则位于双层膜表面。这是首次通过明确的分子动力学证明融合结构域以倾斜方式插入脂质双层膜，并提供了这些肽的插入模式与其融合活性之间的相关性。野生型FP的膜结构与通过核磁共振和电子自旋抗性功率饱和测定的流感HA(2) FP的膜结构非常相似。野生型FP和两个无活性突变体的二级结构相当相似，表明该融合结构域的二级结构在影响融合肽的融合活性方面作用很小或没有作用。野生型FP的插入通过破坏烃链并将界面区域向头部基团区域扩展，增加了双层膜界面区域的厚度，而在无活性的FPs中未观察到这种效果。
