Molecular characterization of the influenza hemagglutinin mediated membrane fusion

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。 它是流感病毒的最重要的毒力因子，并且可能是非常有吸引力的靶点， 新的治疗剂。成功靶向抑制pH诱导的大规模构象 导致膜融合的变化可以有效地防止宿主细胞感染。抗病毒剂 靶向其它病毒蛋白目前仅用于在出现症状后治疗感染。 鉴于HA是典型的I型糖蛋白，HA的机制研究将有助于我们的研究。 了解其他病毒融合子的功能机制。我们的长期目标是 开发一个计算框架，用于合理设计针对特定疾病的新型治疗药物 在一些实施方案中，流感病毒可以通过驱动流感HA介导的膜融合过程的构象重排来表达。我们 这里的总体目标是在原子和热力学水平上准确描述构象， 和HA在生理条件下和在候选药物存在下的结构动力学， 分别解释了由于pH变化和药物结合引起的HA激活和抑制的机制。 虽然目前生物分子模拟研究的范式主要是简单化的模型， 粗粒化（用于大规模构象变化）和对接（用于药物-蛋白质相互作用）以及 更精确和可靠的全原子分子动力学（MD）模拟仅限于相对较短的时间， 时间尺度，我们建议使用微秒级的全原子MD模拟结合统计 基于力学的增强型采样技术，以提供详细、可靠的HA介导的 膜融合机制及其与候选药物的相互作用。建议的理由 研究表明，如果HA介导的膜融合的分子基础得到更好的理解，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 一个主要的流感毒力因子的构象景观，建立一个强大的理性框架 用于设计能够抑制蛋白质介导的膜融合并预防的新型治疗药物 流感病毒感染。该项目将提供研究生，特别是本科生在 阿肯色州大学，有机会在生物医学研究的跨学科领域工作。

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.