Flexibility of the MHC Class II Peptide Binding Cleft in the Bound, Partially Filled, and Empty States: A molecular Dynamics Simulation Study
Flexibility of the MHC Class II Peptide Binding Cleft in the Bound, Partially Filled, and Empty States: A molecular Dynamics Simulation Study
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DOI：
10.1002/bip.21078
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发表时间：
2009-01-01
期刊：
影响因子：
2.9
通讯作者：
Zacharias, Martin
中科院分区：
文献类型：
--
作者：
Yaneva, Rakina;Springer, Sebastian;Zacharias, Martin
主要组织相容性（MHC） II类细胞表面蛋白向免疫系统呈递抗原肽。II类结构与肽复合物，但不知道在没有肽。从CLIP结合的晶体结构开始，对II类蛋白（HLA-DR3）进行了具有和不具有CLIP（不变链相关蛋白）肽的比较分子动力学（MD）模拟。根据P6肽结合口袋中酸性残基的质子化，模拟总体上接近初始结构。没有CLIP的模拟显示出更大的构象波动，特别是结合间隙两侧的α螺旋。在没有CLIP的情况下，在肽c端结合区附近的螺旋段中观察到最大的波动，该螺旋段与空II类蛋白特异性抗体识别的片段相匹配。模拟显示，Val86Tyr突变填充结合P1的肽n端口袋或与P1结合的CLIP片段（二肽）复合物的所有意想不到的远程效应。在这两种模拟中，与没有CLIP的模拟相比，不仅P1的迁移率降低，而且整个结合间隙的迁移率也降低了。这与实验发现，与P1结合的CLIP片段足以阻止抗体识别远离P1的空形式。结果表明，小肽或靠近P1的交换因子的局部结合事件如何通过在接受（近结合）构象中整个结合间隙的长期稳定来促进肽的结合和交换。(C) 2008 Wiley期刊有限公司生物工程学报（英文版），2009。
Major histocompatibility (MHC) Class II cell surface proteins present antigenic peptides to the immune system. Class II structures in complex with peptides but not in the absence of peptide tire known. Comparative molecular dynamics (MD) simulations of a Class II protein (HLA-DR3) with and without CLIP (invariant chain-associated protein) peptide were performed starting from the CLIP-bound crystal structure. Depending on the protonation of acidic residues in the P6 peptide-binding pocket the simulations stayed overall close to the start structure. The simulations without CLIP showed larger conformational fluctuations especially of alpha-helices flanking the binding cleft. Largest fluctuations without CLIP were observed in a helical segment near the peptide C-terminus binding region matching a segment recognized by antibodies specific for empty Class II proteins. Simulations oil a Val86Tyr mutation that fills the peptide N-terminus binding P1 pocket or of a complex with a CLIP fragment (dipeptide) bound to P1 showed all unexpected long range effect. In both simulations the mobility not only of P1 but also of the entire binding cleft was reduced compared to simulations without CLIP. It correlates with the experimental finding that the CLIP fragment binding to P1 is sufficient to prevent antibody recognition specific for the empty form at a site distant from P1. The results suggest a mechanism how a local binding event of small peptides or of an exchange factor near P1 may promote peptide binding and exchange through a long range stabilization of the whole binding cleft in a receptive (near bound) conformation. (C) 2008 Wiley Periodicals, Inc. Biopolymers 91: 14-27, 2009.