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计算机建模和 通过有针对性的结构和功能实验进行模拟，从而可以得到实验结果。 引导回原位研究以迭代改进模型计算的总体目标。 生物学核心（核心B）是利用文献信息、我们的实验结果 编程和从头开始建模，以创建并不断改进分子详细结构模型和 胆固醇流出过程中每个步骤和每个主要参与者的功能假设核心的结构是： 提供以下服务：1）创建模型结构并执行多种分子动力学 (MD) 与每个项目相关的分子模型——SMD、CGMD、STMD 的模拟 2) 细化结构； ABCA1、APOA1 和前一个 PPG 周期中产生的各种 HDL 颗粒 3) 提供平台； 将分子模型与实验数据（化学交联、源自离子的 HDL 粒径）进行比较 迁移率分析、HDL 组成等）。 一种主要工具是构建蛋白质接触图 4) 使用 LOCATE 分析和完善 APOA1 两亲性螺旋结构域相互作用的分子基础， APOA2 和其他载脂蛋白相互之间以及它们与 ABCA1 的相互作用 5) 使用 Rosetta 进行； 从头开始建模和对接（例如 APOA1 与 ABCA1 的相互作用；APOA2 与 APOA1 的相互作用， 核心 B 将由医学博士 Jere Segrest 领导，与范德比尔特大学的 Hyun Song 博士密切合作。 大学医学中心校园，靠近项目 3 所在地。两位研究人员都拥有广泛、良好的研究成果。 记录了核心提议服务的所有领域的专业知识。 执行了数千小时的计算机模拟，生成了数十个详细的分子模型 所有三个项目的实验测试都将对正在进行的研究做出重要贡献。 在此更新周期中提出。