Computational Studies of Early Stage Cell Entry Events by Non-enveloped Viruses

简介（申请人提供）：我目前是美国密歇根大学化学系和生物物理系的博士后。我得到了美国国家科学基金会生物学博士后奖学金的资助。我最初的博士后研究集中在病毒衣壳的机械方面。我开发了一个理论框架和多尺度计算方法，它允许病毒衣壳弹性特性的第一性原理计算。我对了解病毒衣壳弹性特性的兴趣不仅是为了加强纳米技术设计的努力，也是为了了解与病毒生命周期事件相关的衣壳形态变化。到目前为止，我已经进行了几种病毒系统的模拟，包括田菁花叶病毒、豇豆褪绿斑纹病毒、HK97、乙型肝炎病毒和诺瓦克病毒。这项工作对解释病毒的AFM纳米压痕研究具有重要意义。我还对拉沙病毒进行了研究，准确预测了衣壳相关z蛋白的结构及其与几种宿主蛋白的相互作用。随后的实验研究证实了预测的结构。

DESCRIPTION (provided by applicant): I am currently a postdoctoral fellow at the University of Michigan in the departments of Chemistry and Biophysics. I am supported through a National Science Foundation postdoctoral fellowship in biology. My initial postdoctoral research was focused on mechanical aspects of virus capsids. I developed a theoretical framework and multiscale computational methodology, which allows for first-principle calculation of viral capsid elastic properties. My interest in understanding elastic properties of viral capsids is both to enhance nanotechnology design efforts but also to understand morphological changes in capsids related to virus life cycle events. I have conducted simulations of several virus systems so far, including Sesbania mosaic virus, cowpea chlorotic mottle virus, HK97, hepatitis B virus, and Norwalk virus. This work has been impactful in interpreting AFM nanoindentation studies on viruses. I also conducted a study on Lassa virus in which I accurately predicted the structure of the capsid associated Z-protein and its interactions with several host proteins. The predicted structures where confirmed by a subsequent experimental study. My ongoing projects are primarily focused on the maturation transition of HK97. I have been exploring this system in a multiscale approach in which I am using coarse modeling methods to simulate the entire capsid and have constructed a potential to allow the system to transition on a short time scale. I am particularly interested in observing if symmetry breaking occurs during the structural maturation transition. I am also undertaking studies using all-atom models to accurately predict the free energy associated with the maturation transition and detect changes in the free energy surface as a function of pH. While my background to date has been primarily in mechanical properties of biological systems, I am using my remaining time as a postdoc to focus on more biochemically/biomedically relevant problems. I have begun exploring a collaborative project on antibody-target binding free energies. With my collaborator, Dr. Jinny Liu at the Naval Research Labs (see Support Letter), we plan to computationally predict relative binding free energies of mutants of single-domain antibodies-target complexes and experimentally engineer the mutations and test the predictions. My interest in getting involved in antibody research is that I eventually would like to explore virus-antibody interactions and try to understand how the immune system responds to viruses and why many viruses are able to escape detection from the immune system. The proposed project is aimed at understanding events associated with non-enveloped virus entry into cells. The common cues that trigger non-enveloped viruses to undergo conformational changes are pH changes and receptor binding. I have chosen to study a model system for both of these phenomena. Poliovirus is structurally well characterized including a structure in complex with the poliovirus receptor. The receptor binding events induces a conformational change to an uncoating immediate for which there is also a structure. I will conduct studies to understand the free energy associated with receptor binding. I will also study the transition to the uncoating intermediate both in the absence and presence of the receptor. I will also examine how the structure and dynamics of the capsid are altered by receptor binding with particular interest in indentifying pore opening modes, which can release a membrane active peptide from the capsid interior. Flock House virus (FHV) is also structurally well characterized and shares many common features with poliovirus, including the externalization of a membrane active peptide, but the conformational changes are induced by a low pH environment. I will conduct studies to indentify residues that could be responsible for the conformational changes by performing pKa calculations. I will construct model pathways for the release of the membrane active peptide of FHV in close collaboration with Prof. Jack Johnson at Scripps (see Support Letter). For these escape pathways I will compute how the free energy landscape is affected by pH alterations. The work proposed in this project is intended to lay a foundation for further studies on virus infection. I hope to continue this work by examining virus-membrane interactions and the mechanisms of genome release. I also hope to have a component of my lab that will focus on the immune system response to virus invasion. II also have an ongoing collaboration with Prof. Gijs Wuite at VU University Amsterdam, where his lab performs AFM nanoindentation experiments on viruses. His postdoc Dr. Wouter Roos is likely to begin a junior faculty position soon, where he and I will collaborate on mechanics of virus-cell interactions (see Support Letter). It is my goal to obtain a faculty position in a chemical engineering, bio(medical) engineering or biophysics department at a major research institute in the US. The focus of the lab will be on computational and theoretical studies of virus life cycles and infection. I am motivated to understand the physical mechanisms that drive biological systems and make discoveries that can inform experiments and lead to human health benefits. Computational Studies of Early Stage Cell Entry Events by Non-enveloped Viruses.