Structural and Dynamical Determinants of Influenza Transmissibility

季节性流感和大流行性流感都是全球数百万人死亡的原因。仅在美国，季节性流感病毒株的持续每年就造成3000到4.9万人死亡。该项目旨在使用Blue Waters来模拟流感病毒，以解释流感的传播性。这些模拟将是非常大的规模，涉及超过2亿个原子，预计将为流感毒力和耐药性的机制提供前所未有的见解。此外，模拟将为开发对流感感染过程的原子水平的了解的长期目标奠定基础，从而为药物干预提供新的途径。该项目使用了对单个流感膜糖蛋白血凝素(HA)和神经氨酸酶(NA)的分子动力学(MD)模拟，以确定实验验证的抗病毒化合物，这些化合物结合到新的糖蛋白口袋上，这是实验技术从未捕获过的。然而，流感糖蛋白是一个更大的病毒粒子表面的组成部分，共同参与宿主识别和感染过程。表面糖蛋白的分布及其与多糖的修饰提出了许多有趣的悬而未决的问题，涉及HA、NA、多糖以及底物(和底物模拟物)在病毒感染和组装过程中所扮演的角色。此外，HA与宿主细胞受体结合的功能平衡和NA通过裂解末端唾液酸残基取消受体结合的功能平衡尚未完全表征项目要求运行两个完整的病毒粒子模拟的时间：(1)H1N1与HA和NA上的关键糖酵解位点连接的糖链和(2)与唾液酸结合位点的唾液酸结合(模仿底物结合复合体)。加上多糖和底物，这两个体系都将由超过2亿个原子组成。这些模拟将首次将大规模、亚细胞/细胞水平的原子细节建模与马尔可夫状态模型理论相结合；有效地将单个糖蛋白的许多副本聚合到一个基于统计的状态网络类型模型中，使其能够从短时间尺度模拟中提取长时间尺度的动力学。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Both seasonal and pandemic influenza have been responsible for millions of deaths worldwide. The persistence of seasonal influenza strains costs between 3,000 and 49,000 lives annually in the United States alone. The project aims to use Blue Waters to run simulations of the influenza virus to explain flu transmissibility. These simulations will be of a very large scale, involving over 200 million atoms, and are expected to provide unprecedented insights into the mechanisms of influenza virulence and drug resistance. In addition, simulations will set the stage for the longer-term goal of developing an atomic-level understanding of the influenza infection process, leading to new pathways for pharmacological intervention.The project has used molecular dynamics (MD) simulations of the individual influenza membrane glycoproteins hemagglutinin (HA) and neuraminidase (NA) to identify experimentally validated antiviral compounds that bind to new glycoprotein pockets never before captured by experimental techniques. However, influenza glycoproteins are components of a much larger virion surface that collectively participates in host recognition and infection processes. The surface glycoprotein distributions and their decoration with glycans poses many interesting unanswered questions related to the roles of HA, NA, glycans, and substrate (and substrate mimicks) play in the viral infection and assembly process. Additionally, the functional balance of HA, which binds to host-cell receptors, and NA, which abrogates receptor binding via cleavage of terminal sialic-acid residues, has not yet been fully characterized The project request time to run two whole virion simulations: (1) H1N1 with glycans attached to key glycolysation sites on HA and NA and (2) with sialic acid bound in the sialic acid binding sites (mimicking a substrate bound complex). With the addition of the glycans and substrates, both systems will consist of over 200 million atoms. The simulations will for the first time combine large-scale, subcellular / cellular level modeling at atomic detail with Markov state model theory; effectively aggregating the many copies of the individual glycoproteins into one statistics based network of states type model that enables it to extract long timescale dynamics from the short time scale simulations.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.