Permissive Specificity in Peptide Binding to HLA-DR

肽与 HLA-DR 结合的特异性

• 批准号: 8482923
• 负责人: JACK A GORSKI
• 金额: $ 31.31万
• 依托单位: VERSITI WISCONSIN, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8482923
• 关键词: Affect; Affinity; Algorithms; Alleles; Amino Acids; Antigen Presentation; Antigens; Area; Automobile Driving; Binding; Biochemical; Bioinformatics; CD4 Positive T Lymphocytes; Characteristics; Complex; Coupled; DR1 gene; Data; Entropy; Epitopes; Event; Financial compensation; Free Energy; Genetic Polymorphism; Goals; HLA-DR Antigens; Histocompatibility Antigens Class II; Human; Immune response; Informatics; Investigation; Kinetics; Ligands; Major Histocompatibility Complex; Measurable; Measures; Modeling; Molecular; Molecular Conformation; Peptides; Play; Probability; Process; Proteins; Research; Residual state; Role; Site; Specificity; Staging; Surface; System; T cell response; T-Cell Receptor; T-Lymphocyte; Testing; Thermodynamics; Vaccination; Vaccine Design; Validation; base; defined contribution; enthalpy; falls; flexibility; immune function; novel; permissiveness; protein folding; tool; vaccine development

DESCRIPTION (provided by applicant): The adaptive immune response starts when CD4+ T cells recognize peptide antigens presented by class II molecules of the Major Histocompatibility Complex (MHCII). Two outstanding features of MHCII molecules are their polymorphism and the ability of each allele to bind a large panoply of peptides. Our long-term goal is to formally describe the three stages of the peptide recognition process: 1) formation of a peptide-MHCII complex, 2) will the complex be selected for presentation, and 3) will the complex be recognized by a T cell. Predicting epitopes and T cell responses to them is important in two practical areas where MHCII plays a significant role, vaccination and trasnplantation. The goal of the present application is to characterize in detail the first of these three stages, i.e., the prediction of HA-DR (DR) binding peptides. The research proposed here will generate a thermodynamic description of the binding process sufficient to provide a basis for generating predictive algorithms. The ability to predict binding will be an important step in making progress overall. The MHCII and peptides represent a flexible binding system, featuring specificity and permissiveness. This flexibility is evidenced by thermodynamic phenomena, in particular the presence of cooperativity and the occurrence of isothermal entropy-enthalpy compensation (iEEC). Cooperativity is observed in systems where one interaction is affected by other interactions and is associated with protein folding. iEEC describes the ability of entropy (increased search of structural space) to compensate for poorer binding energy (enthalpy). This is the driving mechanism behind permissiveness, in that there is an affinity range in which a peptide with poor binding characteristics has a measurable probability of finding a conformation that allows binding. To include flexibility in a binding prediction model, a deeper understanding of the interaction between cooperativity and iEEC in determining the permissive specificity of peptide binding at the molecular level is needed. To apply our studies to all DR alleles we have to also measure the contribution of the polymorphic cassettes that define the different alleles. Therefore, in Aim 1 we will investigate the energetics involved in peptide/DR complex formation, deconvoluted into enthalpic and entropic components and we will correlate the extent of iEEC to cooperativity. In Aim 2 we will define the biophysical contribution of DR residues to affinity, folding, and energetics to outline a binding model valid for all HLA alleles. Peptide binding usually takes place in the presence of an adjunct molecule, HLA-DM (DM). We have evidence that DM affects peptide binding by setting a permissiveness threshold. Therefore in Aim 3 we will investigate the DR-peptide-DM interaction in thermodynamic terms, correlating DM activity to the thermodynamic signatures of various pDR complexes. In Aim 4 we outline an initial peptide-binding prediction model encompassing the structural and thermodynamic data derived in the first three aims and we propose to validate this approach by predicting binding peptides within randomly generated antigenic sequences.

描述(由申请人提供)：当CD4+T细胞识别主要组织相容性复合体(MHCII)的II类分子呈递的多肽抗原时，适应性免疫反应开始。MHCII分子的两个突出特征是它们的多态和每个等位基因结合大量多肽的能力。我们的长期目标是正式描述肽识别过程的三个阶段：1)形成一个肽-MHCII复合体，2)该复合体将被选择呈现，以及3)该复合体是否被T细胞识别。在MHCII发挥重要作用的两个实际领域，即疫苗接种和移植，预测表位和T细胞对它们的反应是很重要的。本申请的目的是详细描述这三个阶段中的第一个阶段，即预测HA-DR(DR)结合肽。这里提出的研究将产生结合过程的热力学描述，足以为产生预测算法提供基础。预测结合的能力将是取得整体进展的重要一步。MHCII和多肽是一个灵活的结合系统，具有特异性和通透性。热力学现象证明了这种灵活性，特别是协作性的存在和等温熵-热补偿(IEEC)的发生。在一个相互作用受其他相互作用影响并与蛋白质折叠相关的系统中，可以观察到协作性。IEEC描述了熵(增加对结构空间的搜索)来补偿较差的结合能(焓)的能力。这就是放散性背后的驱动机制，因为存在一个亲和力范围，在这个范围内，结合特性较差的多肽有可测量的概率找到允许结合的构象。为了在结合预测模型中包含灵活性，在分子水平上确定多肽结合的允许特异性时，需要更深入地了解协作性和IEEC之间的相互作用。为了将我们的研究应用于所有DR等位基因，我们还必须测量定义不同等位基因的多态盒式磁带的贡献。因此，在目标1中，我们将研究多肽/DR复合体形成过程中涉及的能量学，解卷积成焓和熵分量，并将IEEC的程度与协作性相关联。在目标2中，我们将定义DR残基对亲和力、折叠和能量学的生物物理贡献，以概述一个适用于所有HLA等位基因的结合模型。多肽结合通常发生在一个辅助分子，人类白细胞抗原-DM(DM)的存在。我们有证据表明，DM通过设置一个允许阈值来影响肽结合。因此，在目标3中，我们将从热力学角度研究DR-肽-DM的相互作用，将DM活性与各种PDR络合物的热力学特征相关联。在目标4中，我们概述了一个初始的多肽结合预测模型，该模型包含了前三个目标中得到的结构和热力学数据，并建议通过预测随机生成的抗原序列中的结合多肽来验证该方法。