In silico vaccine design based on molecular simulations of rhinovirus chimeras presenting HIV-1 gp41 epitopes.
In silico vaccine design based on molecular simulations of rhinovirus chimeras presenting HIV-1 gp41 epitopes.
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DOI：
10.1016/j.jmb.2008.10.089
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发表时间：
2009-01-16
影响因子：
5.6
通讯作者：
Levy, Ronald M.
中科院分区：
文献类型：
--
作者：
Lapelosa, Mauro;Gallicchio, Emilio;Arnold, Gail Ferstandig;Arnold, Eddy;Levy, Ronald M.
一组用于开发 HIV 疫苗的有希望的表位位于 HIV 包膜刺突结构的 gp41 亚基的近膜外部区域 (MPER)。对应于所谓的 ELDKWA 表位（HIV-1 HxB2 gp41 残基 662-668）的肽的晶体结构与相应的广泛中和人单克隆抗体 2F5 的复合物为基于结构的疫苗设计策略提供了目标，旨在寻找能够呈现这种具有最佳抗原活性的 MPER 衍生表位的大分子载体。为此，进行了一系列复制品交换分子动力学计算机模拟，以表征插入鼻病毒载体上的基于 ELDKWA 的表位的构象分布，并鉴定具有能够结合 2F5 的最高构象比例的表位。研究发现，长度、疏水特性和精确的插入位点对于实现与目标晶体结构的结构相似性至关重要。获得了与2F5的相应决定区具有高度互补性的构建体。该构建体用于构建 2F5 抗体和嵌合 HRV14:HIV-1 ELDKWA 病毒颗粒之间复合物的高分辨率结构模型。为了研究溶液中 ELDKWA 区域的构象倾向而进行的其他模拟证实了这样的假设：gp41 的 ELDKWA 区域高度灵活，能够呈现螺旋构象（如在融合后螺旋束结构中），以及 β 转角构象（如在与 2F5 抗体的复合物中）。这些结果还表明 ELDKWA 表位可能参与分子内和可能的分子间疏水相互作用。这种趋势为以下观察结果提供了解释：在许多情况下，降低 MPER 疏水特性的突变会导致构象变化，从而增加该区域与 2F5 抗体的亲和力。
A cluster of promising epitopes for the development of HIV vaccines is located in the membrane-proximal external region (MPER) of the gp41 subunit of the HIV envelope spike structure. The crystal structure of the peptide corresponding to the so-called ELDKWA epitope (HIV-1 HxB2 gp41 residues 662–668) in complex with the corresponding broadly neutralizing human monoclonal antibody 2F5 provides a target for structure-based vaccine design strategies aimed at finding macromolecular carriers able to present this MPER-derived epitope with optimal antigenic activity. To this end, a series of replica exchange molecular dynamics computer simulations was conducted to characterize the distributions of conformations of ELDKWA-based epitopes inserted on a rhinovirus carrier and to identify those with the highest fraction of conformations able to bind 2F5. The length, the hydrophobic character, and the precise site of insertion were found to be critical for achieving structural similarity to the target crystal structure. A construct was obtained with a high degree of complementarity to the corresponding determinant region of 2F5. This construct was employed to build a high-resolution structural model of the complex between the 2F5 antibody and the chimeric HRV14:HIV-1 ELDKWA virus particle. Additional simulations, conducted to study the conformational propensities of the ELDKWA region in solution, confirm the hypothesis that the ELDKWA region of gp41 is highly flexible and capable of assuming helical conformations, as in the post-fusion helical bundle structure, as well as β-turn conformations, as in the complex with the 2F5 antibody. These results also suggest that the ELDKWA epitope can be involved in intramolecular and likely intermolecular hydrophobic interactions. This tendency offers an explanation for the observation that mutations decreasing the hydrophobic character of the MPER in many cases result in conformational changes that increase the affinity of this region for the 2F5 antibody.
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影响因子：
56.9
作者：
CONNOLLY, ML
通讯作者：
CONNOLLY, ML
影响因子：
3
作者：
Gallicchio, Emilio;Levy, Ronald M.;Parashar, Manish
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作者：
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影响因子：
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作者：
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通讯作者：
SODROSKI, J
影响因子：
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作者：
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通讯作者：
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