Molecular characterization of the influenza hemagglutinin mediated membrane fusion

流感血凝素介导的膜融合的分子特征

• 批准号: 10047161
• 负责人: Mahmoud Moradi
• 金额: $ 42.26万
• 依托单位: UNIVERSITY OF ARKANSAS AT FAYETTEVILLE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10047161
• 关键词: Antiviral Agents; Appearance; Area; Arkansas; Binding; Biological Models; Biomedical Research; Cells; Docking; Drug Design; Drug Targeting; Environment; Equilibrium; Exposure to; Glycoproteins; Goals; Grain; Hemagglutinin; Infection; Influenza; Influenza Hemagglutinin; Ion Channel; Lead; Light; Mediating; Membrane; Membrane Fusion; Modeling; Molecular; Molecular Conformation; Names; Neuraminidase; Peptides; Pharmaceutical Preparations; Physiological; Process; Proteins; Research; Sampling; Statistical Mechanics; Structure; Symptoms; Techniques; Therapeutic Agents; Thermodynamics; Transmembrane Domain; Universities; Viral; Viral Proteins; Virulence Factors; Virus Diseases; Work; base; clinically significant; combat; computer framework; design; drug candidate; flexibility; influenza virulence; influenzavirus; inhibitor/antagonist; insight; molecular dynamics; new therapeutic target; novel therapeutics; prevent; simulation; targeted agent; targeted treatment; undergraduate student

PROJECT SUMMARY Influenza hemagglutinin (HA) serves as a model system for the study of protein mediated membrane fusion. It is the most important virulence factor for influenza viruses and is potentially a very attractive target for novel therapeutic agents. Successfully targeting the inhibition of pH-induced large-scale conformational changes that lead to membrane fusion could effectively prevent host cell infection. Antiviral agents targeting other viral proteins are currently used to treat infections only after the appearance of symptoms. Given that HA is the canonical type I glycoprotein, mechanistic studies of HA would contribute to our understanding of the functional mechanisms of other viral fusogens as well. Our long-term goal is to develop a computational framework for the rational design of novel therapeutic agents targeting the conformational rearrangements that drive the influenza HA-mediated membrane fusion process. Our overall objective here is to accurately describe, at an atomic and thermodynamic level, the conformational and structural dynamics of HA under physiological conditions and in the presence of candidate drugs to decipher the mechanism of HA activation and inhibition due to pH change and drug binding, respectively. While current paradigm in biomolecular simulation studies is dominated by simplistic models such as coarse graining (for large-scale conformational changes) and docking (for drug-protein interaction) and the more accurate and reliable all-atom molecular dynamics (MD) simulations are limited to relatively short timescales, we propose to use microsecond-level all-atom MD simulations in conjunction with statistical mechanics based enhanced sampling techniques to provide a detailed, reliable account of the HA mediated membrane fusion mechanism and its interactions with candidate drugs. The rationale for the proposed research is that, if the molecular basis of HA-mediated membrane fusion is better understood, we can design more potent therapeutic agents to combat influenza viruses. The proposed research will shed light on the conformational landscape of a major influenza virulence factor, establishing a robust rational framework for the design of novel therapeutic agents that can inhibit protein-mediated membrane fusion and prevent influenza viral infections. This project will provide graduate and particularly undergraduate students at the University of Arkansas with opportunities to work in an interdisciplinary area of biomedical research.

项目摘要 流感血凝素（HA）是研究蛋白质介导的膜融合的模型系统。 它是流感病毒最重要的毒力因素，可能是一个非常有吸引力的目标 新颖的治疗剂。成功地针对抑制pH诱导的大规模构象 导致膜融合的变化可以有效防止宿主细胞感染。抗病毒药 目前，靶向其他病毒蛋白仅在出现症状后才用于治疗感染。 鉴于HA是I型I糖蛋白，HA的机理研究将有助于我们 了解其他病毒融合剂的功能机制。我们的长期目标是 开发一个计算框架，用于针对针对的新型治疗剂的合理设计 驱动流感HA介导的膜融合过程的构象重排。我们的 这里的总体目的是在原子和热力学水平上准确描述构象 在生理条件下以及在存在候选药物下HA的结构动力学 由于pH变化和药物结合，HA激活和抑制作用的机制分别解释了。 虽然生物分子模拟研究中的当前范式主要由简单的模型（例如 粗晶状（用于大规模构象变化）和对接（用于药物蛋白质相互作用）和 更准确和可靠的全原子分子动力学（MD）模拟仅限于相对较短 时间尺度，我们建议将微秒级全部原子MD模拟与统计结合使用 基于力学的增强抽样技术，提供了HA介导的详细，可靠的说明 膜融合机制及其与候选药物的相互作用。提议的理由 研究是，如果更好地理解HA介导的膜融合的分子基础，我们可以设计 更有效的治疗剂来对抗流感病毒。拟议的研究将阐明 主要流感毒力因子的构象景观，建立一个强大的理性框架 为了设计新型治疗剂，可以抑制蛋白质介导的膜融合并防止 流感病毒感染。该项目将为毕业生，尤其是本科生提供 阿肯色大学有机会在生物医学研究的跨学科领域工作。