Computational Biology Core

摘要(核心B) 此计划项目的主要优势之一是在硅胶建模和 有针对性的结构和功能实验的模拟。因此，实验结果可以 引导回现场研究，反复改进模型。计算学的首要目标 生物学核心(核心B)是利用来自文献的信息，来自我们的实验结果 编程和从头算建模，以创建并不断改进分子详细结构模型和 胆固醇流出的每一步和每个主要参与者的功能假说。核心的结构是为了 提供以下服务：1)创建模型结构并执行多种分子动力学 (MD)模拟与每个项目相关的分子模型--SMD、CGMD、STMD；2)改进结构 ABCA1、APOA1和在上一个PPG周期中生成的各种高密度脂蛋白颗粒；3)为 将分子模型与实验数据进行比较(化学交联、离子衍生的高密度脂蛋白颗粒尺寸 迁移率分析、高密度脂蛋白组成等)。一个主要的工具将是构建蛋白质联系图；4)使用 定位分析和提炼APOA1两亲性螺旋结构域相互作用的分子基础， APOA2和其他载脂蛋白之间的相互作用以及它们与ABCA1的相互作用；5)使用Rosetta 从头算建模和对接(例如，APOA1‘S与ABCA1的互动；APOA2’S与APOA1的互动， 等)。核心B将由医学博士Jere Segrest领导，并与Vanderbilt的Hyun Song博士密切合作 大学医学中心校园，靠近项目3所在的地方。两位调查人员都有广泛的，好的- 记录核心拟议服务的所有领域的专门知识。在之前的PPG周期中，核心 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 这三个项目都进行了实验测试。这些模型中的许多将对正在进行的研究做出关键贡献 在这个更新周期中提出的。

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.