Structural Dynamics of Viral Proteins: Computational Investigation of Capsids, Lytic Peptides and Nucleoproteins Under Varying Conditions

这个项目提出了一个多尺度的计算调查阶段的感染过程中的两个 病毒的种类。我们将研究无包膜病毒，以了解膜 这类病毒的破坏。病毒跨膜运输的能力对于感染是必不可少的， 然而，对于无包膜病毒，膜破裂/转运机制的特征很差。非 包膜病毒包括许多公共卫生威胁，如甲型肝炎、戊型肝炎、轮状病毒、科萨基B型病毒 以及每年感染数百万人的鼻病毒。该提案中的研究将集中在两个模型上 系统病毒，感染昆虫，但在这些研究中获得的知识应该可以转移到 人感染无包膜病毒。具体地说，这项建议涉及了解如何溶解 肽是从无包膜病毒衣壳的内部外化的，以及该过程是如何被 博士此外，本研究将集中在相互作用的裂解肽，一旦他们已经外化 从衣壳中分离出来这些相互作用包括膜结合、膜插入、肽寡聚化 和膜机械性能的调节。这些研究的重要发现包括 关于这些感染相关过程的详细结构和能量信息，这将是有价值的 在针对无包膜病毒的抗病毒疗法的开发中。第二类病毒 在这个提议中研究是沙粒病毒，特别是拉沙病毒。拉沙病毒引起出血热， 感染的人，死亡率很高。NIH将拉沙列为A类优先病原体 因为它对公众健康和国家安全构成高风险。这项建议涉及到 了解Lassa核蛋白识别病毒RNA的机制， 核糖核蛋白复合物，其对于病毒复制和转录是必需的。表征强度 这些相互作用的性质将为开发新的抗病毒策略提供机制基础 目标是拉萨在本提案的各个方面，我们将采用多尺度建模方法和新颖的 实验数据将通过多个实验与计算研究相结合， 合作。

This project presents a multiscale computational investigation into stages of the infection process for two classes of viruses. We will study non-enveloped viruses to understand the mechanisms of membrane disruption by this class of virus. The ability of viruses to transport across membranes is essential for infection, yet for non-enveloped viruses the membrane disruption/transport mechanisms are poorly characterized. Non- enveloped viruses include many public health threats such as hepatitis A, hepatitis E, rotavirus, coxsackie B and rhinoviruses, which infect millions of people annually. The studies in the proposal will focus on two model system viruses, which infect insects, but the knowledge gained in these studies should be transferrable to human infecting non-enveloped viruses. Specifically, this proposal is concerned with understanding how lytic peptides are externalized from the interior of non-enveloped virus capsids and how the process is regulated by pH. Additionally, this study will focus on the interactions of the lytic peptides once they have been externalized from the capsid. These interactions include membrane binding, membrane insertion, peptide oligomerization and modulation of membrane mechanical properties. Significant findings from these studies will include detailed structural and energetic information regarding these infection related processes, which will be valuable in the development of anti-viral therapies against non-enveloped viruses. The second class of virus under study in this proposal are Arenaviruses, and specifically Lassa virus. Lassa virus causes hemorrhagic fevers in infected individuals and has high mortality rates. NIH classifies Lassa as a Category A Priority Pathogen because of the high risk it poses to public health and national security. This proposal is concerned with understanding the mechanisms of recognition of viral RNA by the Lassa nucleoprotein and the formation of the ribonucleoprotein complex, which is essential for viral replication and transcription. Characterizing the strength and nature of these interactions will provide the mechanistic basis for development of novel antiviral strategies targeted against Lassa. In all aspects of this proposal we will employ multiscale modeling methods and novel experimental data will be integrated with the computational studies through multiple experimental collaborations.