Binding of antifusion peptides with HIVgp41 from molecular dynamics simulations: Quantitative correlation with experiment
Binding of antifusion peptides with HIVgp41 from molecular dynamics simulations: Quantitative correlation with experiment
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DOI：
10.1002/prot.21301
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发表时间：
2007-05-15
影响因子：
2.9
通讯作者：
Rizzo, Robert C.
中科院分区：
文献类型：
--
作者：
Strockbine, Bentley;Rizzo, Robert C.
基于人类免疫缺陷病毒（HIV病毒蛋白gp 41）的C-末端区域的肽代表了一类重要的新型抗病毒治疗剂，称为肽融合抑制剂。在这项研究中，计算方法被用来模拟6个肽的结合，这些肽含有包装成HIVgp 41上保守的疏水口袋的残基，HIVgp 41是开发小分子抑制剂的有吸引力的靶位点。结合自由能的计算使用分子力学广义玻恩表面积（MM-GBSA）方法从分子动力学（MD）模拟，采用显式（TIP 3 P）或连续广义玻恩（GB）水模型和实验和计算亲和力之间的强相关性，在这两种情况下获得。TIP 3 P-MD 2结果的能量分解（r（2）= 0.75）揭示了在局部（基于残基，r（2）= 0.94）和全局（基于肽，r（2）= 0.84）尺度上，实验亲和力的变化与分子间货车范德华能量（Δ E-vdw）的变化高度相关。结果表明，C肽与HIVgp 41的差异关联仅由保守口袋内的变化驱动，支持该区域是重要药物靶位点的假设。这种与实验的强烈一致性是值得注意的，因为相对于小范围的实验亲和力（2kcal/mol），配体（34个氨基酸）的尺寸较大，并且证明了这种用于模拟肽融合抑制剂的计算方法的良好灵敏度。最后，对模拟轨迹的检查确定了一个高度密集的π型氢键，该氢键在受体上的Gln 575和肽配体Phe 631的芳环之间形成，这可能对药物设计具有重要意义。
Peptides based on C-terminal regions of the human immunodeficiency virus (HIV viral protein gp41 represent an important new class of antiviral therapeutics called peptide fusion inhibitors. In this study, computational methods were used to model the binding of six peptides that contain residues that pack into a conserved hydrophobic pocket on HIVgp41, an attractive target site for the development of small molecule inhibitors. Free energies of binding were computed using molecular mechanics Generalized Born surface area (MM-GBSA) methods from molecular dynamics (MD) simulations, which employed either explicit (TIP3P) or continuum Generalized Born (GB) water models and strong correlations between experimental and computational affinities were obtained in both cases. Energy decomposition of the TIP3P-MD 2 results (r(2) = 0.75) reveals that variation in experimental affinity is highly correlated with changes in intermolecular van der Waals energies (Delta E-vdw) on both a local (residue-based, r(2) = 0.94) and global (peptide-based, r(2) = 0.84) scale. The results show that differential association of C-peptides with HIVgp41 is driven solely by changes within the conserved pocket supporting the hypothesis that this region is an important drug target site. Such strong agreement with experiment is notable given the large size of the ligands (34 amino-acids) relative to the small range of experimental affinities (2 kcal/mol) and demonstrates good sensitivity of this computational method for simulating peptide fusion inhibitors. Finally, inspection of simulation trajectories identified a highly populated pi-type hydrogen bond, which formed between Gln575 on the receptor and the aromatic ring of peptide ligand Phe631, which could have important implications for drug design.