Computational Biology Core

总结（核心B） 该计划项目的主要优势之一是计算机模拟建模的强大互惠关系， 模拟与有针对性的结构和功能实验。因此，实验结果可以 引导回原位研究以迭代地改进模型。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， 编程和从头建模，以创建并不断改进分子详细的结构模型， 功能假说的每一个步骤，每个主要的球员，在胆固醇流出。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)分子模型模拟-SMD，CGMD，STMD-与每个项目相关; 2）细化结构 ABCA 1、APOA 1和前一个PPG周期中产生的各种HDL颗粒; 3）提供一个平台， 将分子模型与实验数据（化学交联，来自离子的HDL颗粒尺寸）进行比较 流动性分析、HDL组成等）。一个主要的工具将是蛋白质接触图的构建; 4）使用 LOCATE分析和完善APOA 1两亲性螺旋结构域相互作用的分子基础， APOA 2和其他载脂蛋白之间的相互作用以及它们与ABCA 1的相互作用; 5）使用Rosetta 从头建模和对接（例如APOA 1与ABCA 1的相互作用; APOA 2与APOA 1的相互作用， 等）。核心B将由Jere Segrest，MD，PhD领导，与范德比尔特的Hyun Song，PhD密切合作 大学医学中心校园，靠近项目3所在地。两位调查员都有大量的，嗯- 在核心建议服务的所有领域都有记录在案的专业知识。在上一个PPG周期中，核心 进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， 三个项目的实验测试。其中许多模型将对正在进行的研究做出重要贡献 在这个更新周期中。

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.