Molecular modeling of an antigenic complex between a viral peptide and a class I major histocompatibility glycoprotein
Molecular modeling of an antigenic complex between a viral peptide and a class I major histocompatibility glycoprotein
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病毒肽和 I 类主要组织相容性糖蛋白之间抗原复合物的分子建模
DOI：
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发表时间：
1992
期刊：
影响因子：
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通讯作者：
G. Folkers
中科院分区：
文献类型：
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作者：
D. Rognan;M. Reddehase;Ulrich H. Koszinowski;G. Folkers
采用计算机模拟游离或与其受体（主要组织相容性复合体（MHC）编码的糖蛋白H-2 Ld）结合的短抗原肽（5-10个残基）的构象，以解释实验确定的抗原活性差异一组相关肽。从模式识别技术揭示的最可能构象开始，对每个序列进行分子动力学模拟（MD），无论是在真空中还是通过水分子溶剂化。值得注意的是，发现抗原效力与肽通过规则i，i+4氢键形成和维持总体α-螺旋构象的倾向相关。因此，活性较低或无活性的肽显示出在其N-末端形成i，i+3氢键的强烈趋势。实验数据证明，C末端残基对于肽与H-2 Ld的相互作用至关重要。这一发现可以通过3D Q.S.A.R.得到满意的解释。配体和受体之间通过疏水力相互作用的分析。提出了高亲和力九肽与H-2 Ld受体之间复合物的三维模型。首先，H-2 Ld分子由两种同源蛋白质的X射线坐标构建：HLA-A2和HLA-Aw 68，能量最小化并通过MD模拟研究。以HLA-A2为模板，实现了溶剂化模型的唯一真实模拟，MD平均结构与X射线构象存在微小偏差。然后用模板衍生的最佳参数实现与抗原性九肽复合的H-2 Ld蛋白的水模拟。结合的肽主要保留其α-螺旋构象，并与对应于MHC蛋白高度多态性位置的H-2 Ld的疏水残基结合。九肽在结合裂隙中的取向与实验测定的其MHC受体结合残基（抗原表位残基）的分布一致。因此，计算机模拟成功地用于解释功能数据并预测结合肽的α螺旋构象。© 1992 Wiley利斯公司
Computer simulation of the conformations of short antigenic peptides (5–10 residues) either free or bound to their receptor, the major histocompatibility complex (MHC)‐encoded glycoprotein H‐2 Ld, was employed to explain experimentally determined differences in the antigenic activities within a set of related peptides. Starting for each sequence from the most probable conformations disclosed by a pattern‐recognition technique, several energy‐minimized structures were subjected to molecular dynamics simulations (MD) either in vacuo or solvated by water molecules. Notably, antigenic potencies were found to correlate to the peptides propensity to form and maintain an overall α‐helical conformation through regular i,i+4 hydrogen bonds. Accordingly, less active or inactive peptides showed a strong tendency to form i,i+3 hydrogen bonds at their N‐terminal end. Experimental data documented that the C‐terminal residue is critical for interaction of the peptide with H‐2 Ld. This finding could be satisfactorily explained by a 3‐D Q.S.A.R. analysis postulating interactions between ligand and receptor by hydrophobic forces. A 3‐D model is proposed for the complex between a high‐affinity nonapeptide and the H‐2 Ld receptor. First, the H‐2 Ld molecule was built from X‐ray coordinates of two homologous proteins: HLA‐A2 and HLA‐Aw68, energy‐minimized and studied by MD simulations. With HLA‐A2 as template, the only realistic simulation was achieved for a solvated model with minor deviations of the MD mean structure from the X‐ray conformation. Water simulation of the H‐2 Ld protein in complex with the antigenic nonapeptide was then achieved with the template‐derived optimal parameters. The bound peptide retains mainly its α‐helical conformation and binds to hydrophobic residues of H‐2 Ld that correspond to highly polymorphic positions of MHC proteins. The orientation of the nonapeptide in the binding cleft is in accordance with the experimentally determined distribution of its MHC receptor‐binding residues (agretope residues). Thus, computer simulation was successfully employed to explain functional data and predicts α‐helical conformation for the bound peptide. © 1992 Wiley‐Liss, Inc.
影响因子：
5.6
作者：
SAPER, MA;BJORKMAN, PJ;WILEY, DC
通讯作者：
WILEY, DC