Structural Dynamics of Viral Proteins: Development and Application of Multiscale Computational Methods for Studying Viral Capsids, Proteins and Membrane Systems

这项提案提出了我未来五年研究计划的愿景。我的实验室正忙于 多尺度计算方法在生物分子系统研究中的应用与发展 驱动人们对无包膜病毒衣壳、生物膜和蛋白质动力学的兴趣。通过这些研究，我们 将提供建模工具，深入了解生物分子功能的调节和机制，并应用 深度学习方法，以获得对蛋白质通讯和构象变化的新理解。 我们研究病毒衣壳的主要动机是了解病毒衣壳的决定因素和分子机制。 感染过程导致衣壳脱壳/解体。我们在病毒系统方面的工作将扩展到 肠道病毒属，包括严重的健康威胁，如脊髓灰质炎病毒、EV-A71和EV-D68。确实有 多种成熟的、未包被的中间体和基因组释放状态的高分辨率结构 肠道病毒使这一研究方向成为可能。这些研究的重要发现将包括详细的 关于病毒感染相关过程的结构和能量信息，这些信息将在 针对这些药物的抗病毒疗法的发展。我们对生物膜的兴趣主要与 双层脂类成分和形状如何影响脂类的结构、动力学和功能性质， 多肽和蛋白质。我们在病毒衣壳和生物膜方面的工作将涉及多分辨率方法 包括原子解析模型和粗粒度模型。对于病毒衣壳，粗粒度模型将是 高级研究脱壳和基因组释放，并将为此开发和分发软件 目的。我们在生物膜方面的工作将得到持续发展和加强我们的 用于构建具有生物灵感形状的弯曲膜系统的BUBPY软件。我们还将研究 先天免疫系统的蛋白质成分，我们将在那里使用有监督的机器学习 对来自不同结构或生化状态的模拟进行分类的方法。使用这些 方法将允许我们定义新的集体变量来计算分子的路径和能量学 识别和激活。对于所有建议的研究，我们将使用先进的多尺度建模方法 并已有或确定了对这些系统有共同兴趣的新的实验合作者，以及 问题，在这些调查中进行合作。

This proposal presents a vision for my research program over the next five years. My lab is engaged in the application and development of multiscale computational methods to study biomolecular systems, with main driver interests in non-enveloped virus capsids, biomembranes and protein dynamics. Through these studies we will provide modeling tools, gain insights into the regulation and mechanisms of biomolecular functions and apply deep learning methods to gain a new comprehension of protein communication and conformational changes. The main motivation in our viral capsid studies is to understand the determinants and molecular mechanisms of infection processes leading to capsid uncoating/disassembly. Our work on virus systems will expand into the genus of Enteroviruses, which include severe health threats such as poliovirus, EV-A71 and EV-D68. There are numerous high resolution structures of mature, uncoating intermediates and genome released states of enteroviruses which enable this research direction. Significant findings from these studies will include detailed structural and energetic information regarding viral infection related processes, which will be valuable in the development of anti-viral therapies against these agents. Our interests in biomembranes are centrally related to how bilayer lipid composition and shape affect the structure, dynamics and functional properties of lipids, peptides and proteins. Our work on virus capsids and biomembranes will involve multi-resolution approaches including atomistically resolved and coarse-grained models. For virus capsids, coarse-grained models will be advanced to study uncoating and genome release and software will be developed and distributed for this purpose. Our work on biomembranes will be supported by the continued development and enhancement of our BUMPy software for constructing curved membrane systems with biologically inspired shapes. We will also study protein components of the innate immune system, where we will employ supervised machine learning approaches to perform classification of simulations from different structural or biochemical states. Using these approaches will allow us to define new collective variables to compute pathways and energetics of molecular recognition and activation. For all the proposed studies we will employ advanced multiscale modeling methods and have existing or identified new experimental collaborators with mutual interest in these systems and questions, to partner with in these investigations.