DYNAMICAL SIMULATIONS OF KINKED DNA AND CRYSTALLOGRAPHIC REFINEMENT BY SIMULATE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 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 摘要： 有必要适当地处理可滴定的基团，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 与其他构型参数相关。这是特别的 在蛋白质-DNA复合体等大分子复合体中具有挑战性， 其中许多可滴定和/或带电基团与 散装溶剂。我们正在开发一种混合分子动力学/蒙特卡罗方法 多直方图(MD/MC-WHAM)恒定pH模拟 和pKa计算。 我们的MC/MC-WHAM组合方法的特点总结如下 以下是： 1)采用显式溶剂，改进了静电模型。 模拟的力场基于微观的Amber8力 Field(1，2)，包括Ewald远程静电学，可选 极化率 2)对每个可滴定部位进行了详细的离散建模 微州。 3)一个仿真周期由MD子周期和MC子周期组成 子周期。MD强制N、P、T恒定，MC强制恒定pH。 这两个子周期一起模拟了一个真正的生化系综常量N、P、T 和pH值。这便于对滴定之间的相关性进行建模 多个位置的状态以及滴定状态和 配置状态。 4)WHAM(5，6)直方图方法简化了全图的计算 热力学参数范围，包括滴定曲线和pKa 价值观。 这项建议是针对下一阶段的发展，即： 1)完全确定以下项的力场修正数 胱氨酸 2)确定给定的统计要求(快照数) 精度水平 3)调查具有两个可滴定位置的系统，以验证 正在模拟适当的交互作用 4)确定第二个氨基酸侧链的修正项 (谷氨酸)

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)