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。 该项目旨在使用蓝色沃茨来模拟流感病毒，以解释流感的传播性。 这些模拟将具有非常大的规模，涉及超过2亿个原子，预计将为流感毒力和耐药性机制提供前所未有的见解。 此外，模拟将为实现对流感感染过程的原子级理解这一长期目标奠定基础，该项目利用分子动力学（MD）模拟了单个流感膜糖蛋白血凝素（HA）和神经氨酸酶（NA），以鉴定实验验证的抗病毒化合物，其结合到以前从未被实验技术捕获的新糖蛋白口袋。 然而，流感糖蛋白是更大的病毒体表面的组分，其共同参与宿主识别和感染过程。 表面糖蛋白分布及其与聚糖的装饰提出了许多有趣的未回答的问题，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，HA（与宿主细胞受体结合）和NA（通过切割末端唾液酸残基消除受体结合）的功能平衡尚未完全表征。（1）H1N1，聚糖连接到HA和NA上的关键糖酵解位点，以及（2）唾液酸结合在唾液酸结合位点（模拟底物结合复合物）。随着聚糖和底物的加入，两个系统都将由超过2亿个原子组成。 模拟将首次将联合收割机大规模、亚细胞/细胞级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拷贝聚合成一个基于统计的状态网络类型模型，使其能够从短时间尺度模拟中提取长时间尺度动力学。该奖项反映了NSF的法定使命，并被认为值得通过以下方式获得支持：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。

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.