COUPLED FOLDING AND BINDING PROCESSES: COMPUTER SIMULATIONS OF THE LACTOSE REPR

耦合折叠和结合过程：乳糖 REPR 的计算机模拟

• 批准号: 7956334
• 负责人: DAVID BARR
• 金额: $ 0.08万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7956334
• 关键词: Algorithms; Automobile Driving; Binding; Biochemical; Biomedical Research; Charge; Computational Science; Computer Retrieval of Information on Scientific Projects Database; Computer Simulation; Coupled; Coupling; DNA; DNA Binding; DNA Sequence; Funding; Grant; High Performance Computing; Institution; Lac Repressors; Lactose; Light; Methods; Motion; Process; Protein Binding; Proteins; Repressor Proteins; Research; Research Personnel; Resources; Rest; Sequence-Specific DNA Binding Protein; Source; System; Thermodynamics; United States National Institutes of Health; Water; Weight; insight; interest; molecular dynamics; protein folding; research study; simulation

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The lac repressor protein is of great biochemical interest because regions of the protein fold as the protein binds a specific DNA sequence and bends the DNA (see attached picture). These coupled protein-folding DNA-binding processes, though common in sequence-specific DNA-binding proteins, prove quite challenging to study. Computational science provides a unique approach to studying this problem by allowing researchers to decouple these two processes and study them independently of each other (impossible in traditional biochemical experiments). I am performing molecular dynamics simulations of the lac repressor protein in its folded and unfolded, bound and unbound states. Specifically, in this project I will use the CHARMM package to perform replica exchange simulations to explore the conformational space of the unfolded lac protein bound to non-specific DNA. Although the system is large (61637 atoms, owing to the need to include explicit water and counterions to offset the charge of the DNA), we have developed advanced biasing algorithms to increase the computational efficiency of these simulations. (H. Kamberaj and A. van der Vaart, JCP, 127, 2007) Thermodynamic information about the system will be obtained from these simulations using the Weighted Histogram Analysis Method and will provide insight into the coupling of folding and binding. In addition, covariance matrices of fluctuations will elucidate the coupling of the motion of the unfolded region to the rest of the protein; these results will be compared to the results of the folded protein bound to specific DNA and will shed light on the molecular interactions that may be responsible for driving local folding upon binding the specific DNA operator.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 LAC抑制剂蛋白具有很大的生化兴趣，因为蛋白质折叠的区域随着蛋白质结合特定的DNA序列并弯曲DNA（请参阅附着的图片）。这些耦合的蛋白质折叠结合过程，尽管在序列特异性的DNA结合蛋白中常见，但研究的研究很具有挑战性。计算科学提供了一种独特的方法来研究此问题，通过允许研究人员将这两个过程解散并彼此独立研究（在传统的生化实验中不可能）。我正在对其折叠和展开，结合和未结合状态进行LAC阻遏蛋白的分子动力学模拟。具体而言，在此项目中，我将使用Charmm软件包执行复制交换模拟，以探索与非特异性DNA结合的展开的LAC蛋白的构象空间。尽管系统很大（61637原子，由于需要包括显式水和柜台以抵消DNA的电荷），因此我们开发了高级偏置算法以提高这些模拟的计算效率。 （H。Kamberaj和A. van der Vaart，JCP，127，2007）有关系统的热力学信息将使用加权直方图分析方法从这些模拟中获得，并将提供有关折叠和结合偶联的洞察力。另外，波动的协方差矩阵将阐明展开区域与蛋白质其余的运动的耦合。这些结果将与与特定DNA结合的折叠蛋白的结果进行比较，并将阐明分子相互作用，这些相互作用可能是在结合特定DNA算子后驱动局部折叠的分子相互作用。