Core D: Structural and Computational Virology

核心D-结构和计算病毒学 摘要 核心D旨在表征与小分子复合的病毒蛋白靶点的结构和动力学 和纳米抗体抑制剂，以支持中西部AViDD中心内的所有项目。结构表征 与抑制剂复合的病毒靶点的研究为合理设计和修饰提供了有价值的框架 从最初的命中阶段，通过铅优化，以及超越小分子的进步。结构 并且这些共复合物的动力学也告知作用机制。在核心D中，我们组装一个 由世界专家组成的协作小组，全面介绍 感兴趣的目标。我们将采用X射线晶体学、低温电子显微镜和核磁共振光谱学， 提供实验表征。随后，计算生物物理技术，包括全原子 分子动力学模拟，计算溶剂映射和其他方法将用于创建 体内目标的精确模型（例如，将来自实验的任何突变恢复为野生型，添加 N-和O-连接的聚糖和其他翻译后修饰），并探索下的目标动力学 相关生理条件。总而言之，我们的集体努力将提供有关 结构和动态的中西部AViDD中心的目标，并加快发现和设计新的， 更安全的药物

Core D – Structural and Computational Virology ABSTRACT Core D aims to characterize the structure and dynamics of viral protein targets in complex with small molecule and nanobody inhibitors, in support of all Projects within the Midwest AViDD Center. Structural characterization of viral targets in complex with inhibitors provides a valuable framework for the rational design and modification of small molecules as they advance from the initial hit stage, through lead optimization, and beyond. Structure and dynamics of these co-complexes also informs on mechanism of action. In Core D, we assemble a collaborative team of world experts to provide comprehensive descriptions of structures and dynamics of targets of interest. We will employ x-ray crystallography, cryoelectron microscopy, and NMR spectroscopy to provide experimental characterization. Subsequently, computational biophysical techniques, including all-atom molecular dynamics simulations, computational solvent mapping, and other methods will be used to create accurate models of the targets in vivo (e.g., with any mutations from experiment reverted to wild type, addition of N- and O-linked glycans and other post-translational modifications) and explore target dynamics under relevant physiological conditions. Altogether, our collective efforts will provide informative insights into the structure and dynamics of Midwest AViDD Center targets, and accelerate the discovery and design of new and safer medications.