Molecular Mechanistic Studies of Antigen-Loading to MHCII Proteins for the Adaptive Immune Recognition by T Cells

MHCII 蛋白负载抗原促进 T 细胞适应性免疫识别的分子机制研究

• 批准号: 352651570
• 负责人: Dr. Sebastian Stolzenberg, Ph.D.
• 金额: --
• 依托单位: Arbeitsgruppe Computergestützte Statistische und Biologische Physik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/352651570?language=en
• 关键词: Molecular; Mechanistic; Studies; Antigen; Loading

Major Histocompatibility Complex class II (MHCII) proteins are biomolecular machines in the immune system that are responsible for the correct loading and presentation of antigenic peptides to T cells; reversely, the dysfunction of these machines is associated with various classes of immune disorders, including allergy, autoimmunity, and immunodeficiency. Important insights into the molecular mechanism of antigen loading to MHCII have been enabled by a number of experimental and computational studies, including X-ray crystallography, NMR spectroscopy, and Molecular Dynamics (MD) simulations. Nevertheless, a molecular mechanistic understanding remains wanted of the detailed conformational dynamics necessary for antigen loading to MHCII, and how these dynamics can be modulated. Therefore, in the proposed research project hosted by Prof. Dr. Frank Noé at Freie Universität Berlin, we will computationally predict these conformational dynamics for phenotypic MHCII mutants and binding partners from an experimentally testable, atomically holistic perspective (i.e. of atoms in the context of entire proteins). To this end, we will establish a synergy between Markov State Modeling (MSM)-based adaptive sampling of MD simulations, protein-wide atomic interaction analyses, and alchemical free energy computations. The successful outcome of this project will be further facilitated through integration into a collaborative network of other excellent scientists, including the experimental group of Prof. Dr. Christian Freund at Freie Universität Berlin, who is an internationally leading expert investigating the molecular mechanism of MHCII antigen loading.

主要组织相容性复合物II类（MHCII）蛋白是免疫系统中负责将抗原肽正确装载和呈递至T细胞的生物分子机器;然而，这些机器的功能障碍与各种类型的免疫疾病相关，包括过敏、自身免疫和免疫缺陷。通过大量的实验和计算研究，包括X射线晶体学、NMR光谱学和分子动力学（MD）模拟，已经能够对抗原加载到MHCII的分子机制进行重要的见解。然而，分子机理的理解仍然需要详细的构象动力学抗原加载到MHCII，以及如何可以调节这些动态。因此，在由Freie Universität柏林的Frank Noé教授主持的拟议研究项目中，我们将从实验可检验的原子整体角度（即整个蛋白质背景下的原子）计算预测表型MHCII突变体和结合伴侣的这些构象动力学。为此，我们将建立基于马尔可夫状态建模（MSM）的MD模拟，蛋白质范围内的原子相互作用分析，和炼金术自由能计算的自适应采样之间的协同作用。该项目的成功结果将通过整合到其他优秀科学家的合作网络中进一步促进，包括Freie Universität柏林的Christian Freund教授博士的实验组，他是研究MHCII抗原加载分子机制的国际领先专家。