Computational Core

计算核心 计算核心将通过提供尖端计算工具和 PCHPI研究人员在确定HIV-1复制的结构和动态基础方面的专业知识 具有原子分辨率的跨多个规模的流程。具体目标旨在：i)全面派生 HIV-1与宿主蛋白复合体与HIV-1胞质转运和核孔相关的动力学模型 贩运，以及二)开发技术以获得蛋白质-脂类以及脂-脂相互作用的分子决定因素 在全面的病毒粒子动力学和真实的脂体成分的背景下。计算核心将 使用规范的分子动力学模拟、增强的抽样计算和 用自由能计算确定小分子对衣壳蛋白复合体动力学的影响 和组件。原位动态模型将处理多达10亿个原子的大规模系统。这些创新之处 这些方法与实验验证相结合，将产生完整的HIV-HIV的完整原子级模型- 1病毒粒子，并提供有关病毒关键过程的结构和动力学的变革性信息 复制周期，以指导新的治疗干预措施的开发。

Computational Core The computational core will support the three PCHPI projects by providing cutting-edge computational tools and expertise to PCHPI researchers for determining structural and dynamic bases underlying HIV-1 replication processes across multiple scales, with atomic resolution. Specific aims are designed to: i) derive full-scale dynamic models of HIV-1 and host protein complexes related to HIV-1 cytosolic transport and nuclear pore trafficking, and ii) develop techniques to derive molecular determinants of protein-lipid, and lipid-lipid interactions in the context of full-scale virion dynamics and realistic lipidomic compositions. The computational core will design methodologies using canonical molecular dynamics simulations, enhanced sampling calculations and free energy calculations to determine the effects of small molecules on the dynamics of capsid protein complexes and assemblies. In-situ dynamic models will address large-scale systems, up to a billion atoms. These innovative approaches, in conjunction with experimental validations, will yield a complete atomic-level model of intact HIV- 1 virions and provide transformative information about structures and dynamics of key processes in the viral replication cycle, to guide the development of new therapeutic interventions.