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首页> 美国卫生研究院文献>Protein Science : A Publication of the Protein Society >Design of enhanced agonists through the use of a new virtual screening method: Application to peptides that bind class I major histocompatibility complex (MHC) molecules
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Design of enhanced agonists through the use of a new virtual screening method: Application to peptides that bind class I major histocompatibility complex (MHC) molecules

机译：通过使用新的虚拟筛选方法设计增强的激动剂：应用于结合I类主要组织相容性复合体（MHC）分子的肽

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摘要

A new screening procedure is described that uses docking calculations to design enhanced agonist peptides that bind to major histocompatibility complex (MHC) class I receptors. The screening process proceeds via single mutations of one amino acid at the positions that directly interact with the MHC receptor. The energetic and structural effects of these mutations have been studied using fragments of the original ligand that vary in length. The results of these docking studies indicate that the mutant affinity ranking of long peptides can be practically reproduced with a screening approach performed using fragments of six residues. Fragments of four and five residues could mimic, in some cases, the structural arrangement of the side chains of the full-length peptide. We have compared the structural and energetic results of the docking calculations with experimental data using three unrelated ligand peptides that differ greatly in their affinity for the MHC complex. Analysis of the affinity of the fragments led to the identification of three important parameters in the construction of fragments that mimic the structural and energetic properties of the full-length ligand: the length of the fragment; its intermolecular energy; and the number and localization, internal or terminal, of the anchor residues. The results of this new peptide-design methodology have been applied to suggest new peptides derived from the MUC1–8 peptide that could be used as murine vaccines that trigger the immune response through the MHC class I protein H-2Kb.
机译：描述了一种新的筛选程序，该程序使用对接计算来设计与主要组织相容性复合物（MHC）I类受体结合的增强型激动剂肽。筛选过程通过与MHC受体直接相互作用的位置上一个氨基酸的单突变进行。已经使用长度可变的原始配体的片段研究了这些突变的能量和结构效应。这些对接研究的结果表明，长肽的突变亲和力等级实际上可以通过使用六个残基的片段进行的筛选方法来重现。在某些情况下，四个和五个残基的片段可以模拟全长肽的侧链的结构排列。我们已经使用三种不相关的配体肽对接计算的结构和能量结果与实验数据进行了比较，这三种配体肽对MHC复合物的亲和力差异很大。片段亲和力的分析导致在片段构建中鉴定了三个重要参数，这些参数模仿了全长配体的结构和能量特性：片段的长度；它的分子间能量；以及锚残基的数量和位置（内部或末端）。这种新的肽设计方法的结果已被用于暗示从MUC1-8肽衍生的新肽，可用作鼠类疫苗，可通过MHC I类蛋白H-2K b触发免疫反应。。

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