Vaccaro Loredana, Cross Karen J, Kleinjung Jens, Straus Suzana K, Thomas David J, Wharton Stephen A, Skehel John J, Fraternali Franca
National Institute for Medical Research, London, United Kingdom.
Biophys J. 2005 Jan;88(1):25-36. doi: 10.1529/biophysj.104.044537. Epub 2004 Oct 8.
A detailed molecular dynamics study of the haemagglutinin fusion peptide (N-terminal 20 residues of the HA2 subunits) in a model bilayer has yielded useful information about the molecular interactions leading to insertion into the lipids. Simulations were performed on the native sequence, as well as a number of mutant sequences, which are either fusogenic or nonfusogenic. For the native sequence and fusogenic mutants, the N-terminal 11 residues of the fusion peptides are helical and insert with a tilt angle of approximately 30 degrees with respect to the membrane normal, in very good agreement with experimental data. The tilted insertion of the native sequence peptide leads to membrane bilayer thinning and the calculated order parameters show larger disorder of the alkyl chains. These results indicate that the lipid packing is perturbed by the fusion peptide and could be used to explain membrane fusion. For the nonfusogenic sequences investigated, it was found that most of them equilibrate parallel to the interface plane and do not adopt a tilted conformation. The presence of a charged residue at the beginning of the sequence (G1E mutant) resulted in a more difficult case, and the outcomes do not fall straightforwardly into the general picture. Sequence searches have revealed similarities of the fusion peptide of influenza haemagglutinin with peptide sequences such as segments of porin, amyloid alpha eta peptide, and a peptide from the prion sequence. These results confirm that the sequence can adopt different folds in different environments. The plasticity and the conformational dependence on the local environment could be used to better understand the function of fusion peptides.
对模型双分子层中血凝素融合肽（HA2亚基的N端20个残基）进行的详细分子动力学研究，已得出有关导致插入脂质的分子相互作用的有用信息。对天然序列以及许多融合或非融合的突变序列进行了模拟。对于天然序列和融合突变体，融合肽的N端11个残基呈螺旋状，并以相对于膜法线约30度的倾斜角插入，这与实验数据非常吻合。天然序列肽的倾斜插入导致膜双分子层变薄，计算得到的序参数显示烷基链的无序度更大。这些结果表明脂质堆积受到融合肽的干扰，可用于解释膜融合。对于所研究的非融合序列，发现它们中的大多数与界面平面平行达到平衡，不采取倾斜构象。序列起始处存在带电荷残基（G1E突变体）导致情况更为复杂，结果并不直接符合总体情况。序列搜索揭示了流感血凝素融合肽与肽序列的相似性，如孔蛋白片段、淀粉样α肽和朊病毒序列中的一个肽段。这些结果证实该序列在不同环境中可采取不同的折叠方式。可塑性和构象对局部环境的依赖性可用于更好地理解融合肽的功能。
