Development Of Theoretical Methods For Studying Biologic

新的理论技术正在被开发和表征。这些工作通常与软件开发结合在一起，并涉及对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： -开发电子密度图对接实用程序(EMAP) -根据EM图谱构建分子组装的核心加权拟合法 -使用低分辨率地图的分子建模 -自导分子动力学(SGMD)模拟中的热力学性质 -计算长程相互作用的有效方法 截断范德华(LJ)相互作用的各向异性长程校正 -开发和验证在P21边界条件下模拟界面系统的方法(单面) -检查高分辨率蛋白质结构中的氢键--一种评估核磁共振蛋白质几何结构的新方法 -使用从头计算研究对局部蛋白质结构的依赖性来检查酰胺质子移位张量 -发展研究复杂体系中反应机理的方法 -对复杂构象转变的无偏强制采样和沿反应路径的平均作用力势的估计 -开发使用模拟退火法确定复杂体系中的反应路径的复制/路径方法 -发展组合量子力学/分子模型(QM/MM)势(高斯离域MM电荷，双链原子方法) -用于QM/MM应用程序的GamesS-UK和CHARMM集成 -使用双链原子界面的密度泛函QM/MM -评估QM/MM界面的替代处理 -发展精确的大分子相互作用能计算 -开发用于对接两个大分子的快速搜索策略 -开发高效和准确的溶剂化模型，使用水溶液模拟来提供溶剂化力信息。 在分子建模和使用低分辨率图谱确定结构方面已经做出了相当大的努力。这涉及到CHARMM中电子密度图对接实用程序(EMAP)模块的开发。已为该模块开发了核心加权拟合方法，并已被证明能很好地根据电子显微镜(EM)图构建分子组装。 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。为了研究酶的作用机制，实验室开发了“高斯模糊双键原子(DLA/DGMM)”技术。GamesS-UK已紧密集成到CHARMM中，以便研究小分子和酶复合体中的催化路径。这扩展了CHARMM中的QM/MM套件，因为GamesS-UK提供了DFT方法。 在与Ichiye Toshiko教授的合作下，正在努力改进和进一步开发新的液态水势能函数，这对于在现实环境中精确的生物分子计算机模拟至关重要。水模型被称为软粘性偶极子(SSD)模型，它比目前使用的模型更快、更准确。目前的重点是将电子极化率添加到SSD水中，这将增强在特殊环境中对水进行建模的能力，例如在膜孔和通道内或靠近金属位置。

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. The core-weighted fitting method has been developed for this module and has been demonstrated to work well for constructing molecular assemblies from electron microscopy (EM) maps. 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.