Computational Biology Core

计算生物学核心

• 批准号: 10711259
• 负责人: Jere P Segrest
• 金额: $ 19.18万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10711259
• 关键词: APOA5 gene; ATP-Binding Cassette Transporters; Academic Medical Centers; Apolipoprotein A-I; Apolipoprotein A-II; Apolipoprotein E; Apolipoproteins; Apolipoproteins A; Apolipoproteins C; Area; Back; Cardiovascular Diseases; Chemicals; Cholesterol; Collaborations; Computational Biology; Computer Simulation; Data; Docking; Doctor of Philosophy; Exhibits; Experimental Models; Goals; Grain; Heterogeneity; High Density Lipoproteins; Hour; In Situ; Lipids; Literature; Maps; Membrane; Modeling; Molecular; Molecular Conformation; Particle Size; Phospholipids; Process; Program Research Project Grants; Property; Proteins; Research Personnel; Services; Structural Models; Structure; Testing; Trefoil; Visualization; apolipoprotein A-IV; crosslink; experimental study; improved; in silico; interdisciplinary approach; ion mobility; models and simulation; molecular dynamics; molecular modeling; novel; particle; programs; tool; translocase

SUMMARY (Core B) One of the key strengths of this Program Project is the powerful reciprocal relationship of in silico modeling and simulation with targeted structural and functional experimentation. Thus, experimental results can be channeled back into in situ studies to iteratively improve models. The overarching goal of the Computational Biology Core (Core B) is to take advantage of information from the literature, experimental results from our Program, and ab initio modeling to create, and continually improve, molecularly detailed structural models and functional hypotheses for each step, and each major player, in cholesterol efflux. The core is structured to provide the following services: 1) create model structures and perform several varieties of molecular dynamics (MD) simulations of molecular models—SMD, CGMD, STMD—relevant to each Project; 2) refine structures of ABCA1, APOA1, and various HDL particles generated during the previous PPG cycle; 3) provide a platform for comparing molecular models to experimental data (chemical crosslinking, HDL particle sizes derived from ion mobility analyses, HDL composition, etc.). One primary tool will be construction of protein contact maps; 4) use LOCATE to analyze and refine the molecular basis for interactions of amphipathic helical domains of APOA1, APOA2, and other apolipoproteins with each other as well as their interactions with ABCA1; 5) use Rosetta for ab initio modeling and docking (e.g. APOA1’s interactions with ABCA1; APOA2’s interactions with APOA1, etc.). Core B will be led by Jere Segrest, MD, PhD, working closely with Hyun Song, PhD, at Vanderbilt University Medical Center campus, near where Project 3 is located. Both investigators have extensive, well- documented expertise in all areas of the Core’s proposed services. In the previous PPG cycle, the Core executed thousands of hours of computer simulations that generated dozens of detailed molecular models for experimental testing by all three Projects. Many of these models will contribute critically to the ongoing studies proposed in this renewal cycle.

摘要（核心B） 该计划项目的关键优势之一是在计算机建模和 靶向结构和功能实验的模拟。那可以是 回到原位研究中，以改善模型。计算的总体目标 生物学核心（核心B）是利用文献中的信息，我们的实验结果 程序和从头算建模，以创建并不断改进分子详细的结构模型，并 胆固醇外排的每个步骤和每个主要参与者的功能假设。核心结构为 提供以下服务：1）创建模型结构并执行分子动力学的几种变体 （MD）分子模型的仿真-SMD，CGMD，STMD-对每个项目的模拟； 2）完善的结构 在上一个PPG周期中产生的ABCA1，APOA1和各种HDL颗粒； 3）提供一个平台 将分子模型与实验数据进行比较（化学交联，HDL粒度源自离子 移动性分析，HDL组成等）。一个主要工具将是构建蛋白质接触图。 4）使用 定位以分析和完善apoA1两亲性螺旋结构域相互作用的分子基础 apoA2和其他载脂蛋白彼此之间以及它们与ABCA1的相互作用； 5）将Rosetta用于 从头开始建模和对接（例如，apoa1与ABCA1; apoA2与apoa1的互动， ETC。）。核心B将由医学博士Jere Segrest领导，并与Hyun Song，PhD紧密合作 大学医学中心校园，附近的项目3。两位调查人员都有广泛的 在核心拟议服务的所有领域中都记录了专业知识。在上一个PPG周期中，核心 执行了数千个小时的计算机模拟，以生成数十个详细的分子模型 所有三个项目的实验测试。这些模型中的许多将为正在进行的研究做出巨大贡献 在此更新周期中提出。