Integrative modeling core

综合建模核心

• 批准号: 10512623
• 负责人: ANDREJ SALI
• 金额: $ 399.95万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-16 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10512623
• 关键词: 2019-nCoV; 5' Untranslated Regions; Address; Binding; Biochemistry; Biological Models; Bypass; Capsid; Chemicals; Collaborations; Complex; Coupling; Cryo-electron tomography; Cryoelectron Microscopy; Crystallization; Crystallography; Data; Data Set; Deuterium; Docking; Fluorine; Goals; Grain; Heterogeneity; Hydrogen; Image; In Vitro; Ligand Binding; Ligands; Machine Learning; Maps; Mass Spectrum Analysis; Methods; Modeling; Molecular Conformation; Nuclear; Oligonucleotides; Proteins; Proteome; Proteomics; Resolution; Roentgen Rays; Side; Structural Models; Structure; Structure-Activity Relationship; System; Temperature; Variant; Viral; Viral Proteins; Virus-like particle; X ray diffraction analysis; X-Ray Crystallography; atomic state; base; crosslink; design; dimer; drug discovery; in vivo; multiple myeloma M Protein; open source; pandemic disease; particle; preference; programs; protein E; reconstruction; response; structural biology

CORE 5: INTEGRATIVE MODELING CORE SUMMARY We aim to enable Projects and other Cores to perform structure-based discovery and optimization of ligands for viral protein targets. This goal will be achieved by developing and applying our unique integrative modeling toolbox to compute structural models of the target viral systems, based on varied experimental data from other Cores and Projects. The key challenge in obtaining these models is structural heterogeneity of viral proteins, including large variations in secondary structure content and domain orientations as well as small variations in loop and side chain conformations. Accurate, precise, and complete description and characterization of these multiple states is key to understanding and modulating their functions with ligands. We hypothesize that explicit modeling of multiple conformations of viral proteins is especially needed: Viral proteomes may have evolved to exploit the multiplicity of conformations for delivering function more than the proteomes that are not constrained to a small number of short proteins. We will address this challenge in two ways. First, coarse-grained structural models (Aim 1), based on limited information from cryo-electron microscopy, cryo-electron tomography, chemical cross-linking, and footprinting, will provide an essential step to atomic structures; for example, via design of variants suitable for X-ray crystallography and starting models for high-resolution single particle cryo- EM reconstruction. Second, multi-state atomic models of viral proteins that explicitly describe their heterogeneity will be computed based on data from X-ray crystallography (Aim 2), cryo-electron microscopy (Aim 3), and ligand structure-activity relationship (SAR) studies (Aim 4). Our multi-state models will help reveal static, dynamic, and even cryptic binding pockets of viral proteins, which, in turn, will facilitate ligand discovery and optimization. All Cores and Projects will rely on our models.

核心5：集成建模 核心摘要 我们旨在使项目和其他核心能够对配体进行基于结构的发现和优化 病毒蛋白靶标。这一目标将通过开发和运用我们独特的集成建模来实现 基于其他来自其他的实验数据来计算目标病毒系统的结构模型的工具箱 核心和项目。获得这些模型的主要挑战是病毒蛋白的结构异质性， 包括二级结构内容和域取向的较大变化，以及较小的变化 循环和侧链构象。精确，精确且完整的描述和表征 多个状态是理解和调节配体功能的关键。我们假设这是明确的 特别需要对病毒蛋白的多种构象进行建模：病毒蛋白质组可能已经演变为 比不受限制的蛋白质组织利用多种构象的多样性 到少数短蛋白。我们将通过两种方式解决这一挑战。首先，粗粒结构 模型（AIM 1），基于Cryo-Electron显微镜，冷冻电子断层扫描的有限信息， 化学交联和足迹将为原子结构提供重要步骤。例如，通过 适用于X射线晶体学和高分辨率单个粒子冷冻模型的变体设计 EM重建。其次，明确描述其异质性的病毒蛋白的多态原子模型 将根据X射线晶体学（AIM 2），冷冻电子显微镜（AIM 3）和 配体结构活性关系（SAR）研究（AIM 4）。我们的多状态模型将有助于揭示静态， 病毒蛋白的动态，甚至神秘的结合袋，而这又会促进配体发现和 优化。所有核心和项目都将依靠我们的模型。