Development Of Theoretical Methods For Studying Biologic

新的理论技术正在发展和特点。这些工作通常与软件开发相结合，并涉及新想法的系统测试和评估。这一发展是由当前的需求和利益驱动的。 正在进行的具体项目包括： - 电子密度图对接工具（EMAP）的开发 - 由EM图构造分子组装体的核加权拟合方法 - 使用低分辨率图的分子建模 - 自导引分子动力学（SGMD）模拟中的热力学性质 - 一种计算长程相互作用的有效方法 - 截断货车德瓦尔（LJ）相互作用的各向异性长程修正 - P21边界条件下界面系统模拟方法的开发和验证（单表面） - 在高分辨率蛋白质结构中检查氢键--一种评估NMR蛋白质几何结构的新方法 - 用从头算方法研究酰胺质子位移张量对蛋白质局部结构的依赖性 - 复杂体系反应机理研究方法的进展 - 复杂构象转变的无偏强制采样和反应途径平均力沿着的势估计 - 用模拟退火确定复杂体系反应路径的REPLICA/PATH方法的发展 - 开发组合量子力学/分子模拟（QM/MM）势（高斯离域MM电荷，双键原子方法） - 用于QM/MM应用的GAMESS-UK和CHARMM集成 - 基于双键原子界面的密度泛函QM/MM - QM/MM界面替代治疗的评价 - 高分子相互作用能精确计算方法的发展 - 一种用于对接两个大分子的快速搜索策略的发展 - 利用水溶液模拟开发高效准确的溶剂化模型，提供溶剂化力信息。 相当大的努力已经针对分子建模和结构测定使用低分辨率地图。这涉及CHARMM中的电密度图对接实用程序（EMAP）模块的开发。我们已经开发了一种核心加权方法来将原子结构拟合到具有多个组分的生物分子组装的低分辨率EM图中。与更传统的相关性相比，所提出的核心加权相关性显著提高了区分正确拟合的灵敏度。因此，复杂大分子组装体的分子模型的构建从多体搜索问题简化为一系列单体搜索问题，使得计算搜索正确的拟合容易得多。结合核加权相关函数，提出了一种网格线程蒙特卡罗（GTMC）方法，以有效地搜索最佳拟合。 量子力学/分子力学（QM/MM）技术在酶机制中竞争反应途径的理论研究中非常有用。该实验室开发了“双连接原子与高斯模糊（DLA/DGMM）”技术，用于研究酶的机制。GAMESS-UK已被紧密集成到CHARMM中，以允许研究小分子和酶复合物中的催化途径。这扩展了CHARMM中的QM/MM套件，因为GAMESS-UK提供DFT方法。 与Toshiko Ichiye教授合作，正在努力完善和进一步开发液态水的新势能函数，这对于在现实环境中准确模拟生物分子至关重要。被称为软粘性偶极子（SSD）模型的水模型比目前使用的模型更快，更准确。目前，重点是将电子极化性添加到SSD水中，这将增强在特定环境中模拟水的能力，例如在膜孔和通道内或金属部位附近。

New theoretical techniques are being developed and characterized. These efforts are usually coupled with software development, and involve the systematic testing and evaluation of new ideas. This development is driven by current needs and interests. Specific ongoing projects include: - Development of electric density map docking utility (EMAP) - The core-weighted fitting method to construct molecular assemblies from EM maps - Molecular modeling using low resolution maps - Thermodynamic properties in Self-Guided Molecular Dynamics (SGMD) simulations - Efficient approach for the calculation of long range interactions - Anisotropic long range corrections for truncated van der Waal (LJ) interactions - Development and validation of methods for simulating interfacial systems in P21 boundary conditions (single surface) - Examining hydrogen bonding in high-resolution protein structures a new method to assess NMR protein geometry - Examining amide proton shift tensor using an ab initio study of dependence on local protein structure - Development of methods for examining reaction mechanism in complex systems - Unbiased forced sampling of complex conformational transitions and estimation of the potential of mean force along the reaction pathway - Development of the REPLICA/PATH method for determining reaction paths in complex systems using simulated annealing - Development of combined Quantum Mechanical/Molecular Modeling (QM/MM) potentials (Gaussian delocalize MM charges, double link atom method) - GAMESS-UK and CHARMM integration for QM/MM applications - Density functional QM/MM using a double link atom interface - Evaluation of alternate treatments of QM/MM interfaces - Development of accurate interaction energy calculations for macromolecules - Development of a rapid search strategy for docking two macromolecules - Development of efficient and accurate solvation model using aqueous solution simulation to provide solvation force information. Considerable efforts has been aimed at molecular modeling and structure determination using low resolution maps. This involved the development of electric density map docking utility (EMAP) module in CHARMM. we have developed a core-weighting approach to fit atomic structures into low resolution EM maps of biomolecular assembly with multiple components. The proposed core-weighted correlations have significantly improved sensitivity to distinguish the correct fit when compared with more traditional correlations. The construction of a molecular model for a complex macromolecular assembly is thus simplified from a many-body search problem to a series of single-body search problems, making the computational search for the correct fit much easier. Combined with the core-weighted correlation function, a grid-threading Monte Carlo (GTMC) approach is developed to search the best fit efficiently. Quantum mechanical/molecular mechanical (QM/MM) techniques are extremely useful in the theoretical examination of competing reaction pathways in enzyme mechanisms. The laboratory has developed the 'Double link atoms with gaussian blur (DLA/DGMM)' technique for the purpose of studying enzyme mechanisms. GAMESS-UK has been tightly integrated into CHARMM to allow studies of catalytic paths in small molecules and enzyme complexes. This extends the QM/MM suite within CHARMM since GAMESS-UK provides DFT methods. In collaboration with Prof. Toshiko Ichiye, there is an ongoing effort to refine and further develop a new potential energy function for liquid water, which is crucial for accurate computer simulations of biological molecules in realistic environments. The water model, which is referred to as the soft sticky dipole (SSD) model, is both faster and more accurate than currently used models. Currently, the focus is on adding electronic polarizability into SSD water, which will enhance the ability to model water in specialized environments such as inside membrane pores and channels or near metal sites.