DYNAMICAL SIMULATIONS OF KINKED DNA AND CRYSTALLOGRAPHIC REFINEMENT BY SIMULATE

扭结 DNA 的动态模拟和通过模拟进行的晶体细化

• 批准号: 7723102
• 负责人: JOHN M ROSENBERG
• 金额: $ 0.05万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7723102
• 关键词: Amino Acids; Basic Amino Acids; Biochemical; Charge; Complex; Computer Retrieval of Information on Scientific Projects Database; Cystine; Development; Electrostatics; Funding; Glutamic Acid; Grant; Hybrids; Institution; Macromolecular Complexes; Methods; Microscopic; Modeling; Numbers; Proteins; Range; Research; Research Personnel; Resources; Side; Simulate; Site; Solvents; Source; Staging; System; Thermodynamics; Titrations; United States National Institutes of Health; Weight; abstracting; base; improved; models and simulation; molecular dynamics; 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. Keywords: Molecular Dynamics, Monte Carlo, Weighted Histograms, constant pH simulation, pKa calculation Abstract: It is necessary to properly treat titratable groups, such as acidic or basic amino acid residues, during the course of a molecular dynamics simulation, especially since fluctuations in titration states are expected to be correlated with other configurational parameters. This is especially challenging in macromolecular complexes such as protein-DNA complexes, where many titratable and/or charged groups are a significant distance from bulk solvent. We are developing a hybrid Molecular Dynamics/Monte Carlo-Multiple Histogram (MD/MC-WHAM) method for constant pH simulations and pKa calculations. A summary of the features of our combined MC/MC-WHAM approach is as follows: 1) Explicit solvent is used, improving the electrostatic modeling. The simulation force field is based on the microscopic Amber8 Force Field(1,2), which includes Ewald long-range electrostatics, and optional polarizability 2) Each titratable site is modeled in detail with discrete microstates. 3) One simulation cycle consists of an MD sub-cycle and an MC sub-cycle. The MD enforces constant N,P,T and the MC enforces constant pH. Together both sub-cycles model a true biochemical ensemble, constant N,P,T and pH. This facilitates modeling of correlations between the titration states at multiple sites as well as between titration states and configuration states. 4) WHAM(5,6) histogram methods facilitate the calculation of a full range of thermodynamic parameters, including titration curves and pKa values. This proposal is for the next stages of development, which are to: 1) Complete determination of the force field correction number for Cystine 2) Determine statistical requirements (# of snapshots) for given levels of precision 3) Investigate system with two titratable sites to verify that appropriate interactions are being simulated 4) Determine the correction term for a second amino acid side chain (Glutamic acid)

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 关键词：分子动力学、蒙特卡罗、加权直方图、恒定 pH 模拟、pKa 计算 抽象的： 有必要正确处理可滴定基团，例如酸性或 分子动力学过程中的碱性氨基酸残基 模拟，特别是因为滴定状态的波动是预期的 与其他配置参数相关。 这尤其是 在蛋白质-DNA 复合物等大分子复合物中具有挑战性， 其中许多可滴定和/或带电基团与 本体溶剂。 我们正在开发混合分子动力学/蒙特 用于恒定 pH 模拟的卡洛多重直方图 (MD/MC-WHAM) 方法 和 pKa 计算。 我们组合的 MC/MC-WHAM 方法的特征总结如下 如下： 1）使用显性溶剂，改善静电建模。 模拟力场基于微观Amber8 Force Field(1,2)，包括 Ewald 远程静电场，以及可选的 极化率 2) 每个可滴定位点均采用离散模型进行详细建模 微观状态。 3) 一个仿真周期由一个MD子周期和一个MC组成 子循环。 MD 强制执行恒定的 N、P、T，MC 强制执行恒定的 pH。 两个子循环一起模拟一个真正的生化整体，恒定的 N、P、T 和pH值。 这有助于对滴定之间的相关性进行建模 多个位点的状态以及滴定状态之间的状态 配置状态。 4) WHAM(5,6)直方图方法有助于计算完整的 热力学参数范围，包括滴定曲线和 pKa 价值观。 该提案针对下一阶段的开发，即： 1) 完成力场修正数的确定 胱氨酸 2) 确定给定的统计要求（快照数量） 精度等级 3) 研究具有两个可滴定位点的系统以验证 正在模拟适当的交互 4) 确定第二个氨基酸侧链的校正项 （谷氨酸）