Structural and Dynamical Determinants of Influenza Transmissibility

季节性流感和大流行性流感已造成全世界数百万人死亡。仅在美国，季节性流感病毒株的持续存在每年就造成3,000至49,000人死亡。该项目旨在利用Blue Waters对流感病毒进行模拟，以解释流感的传播性。这些模拟将是一个非常大的规模，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，模拟将为发展对流感感染过程的原子水平理解的长期目标奠定基础，从而为药物干预开辟新的途径。该项目使用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）模拟来鉴定实验验证的抗病毒化合物，这些化合物与以前从未被实验技术捕获的新糖蛋白口袋结合。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。糖蛋白的表面分布及其与聚糖的修饰提出了许多有趣的悬而未决的问题，这些问题与HA、NA、聚糖和底物（和底物模拟物）在病毒感染和组装过程中的作用有关。此外，与宿主细胞受体结合的透明质酸和通过末端唾液酸残基切割而消除受体结合的NA的功能平衡尚未得到充分表征。该项目需要时间进行两个完整的病毒粒子模拟：(1)H1N1病毒与HA和NA的关键糖酵解位点上的聚糖结合；(2)唾液酸结合在唾液酸结合位点上（模拟底物结合复合物）。加上聚糖和底物，这两个体系将由超过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结合起来；将单个糖蛋白的多个拷贝有效地聚合到一个基于状态网络的统计模型中，使其能够从短时间尺度的模拟中提取长时间尺度的动态。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值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.