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各向同性周期和方法 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) -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 -发展用于从头计算组合量子力学/分子模拟的线性标度方法 -增强QM/MM势(使用高斯离域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 -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 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。我们开发了一种核加权方法，将原子结构匹配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敏感度。因此，复杂大分子组装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变得容易得多。结合核加权相关函数，提出了一种网格-线程蒙特卡罗(GTMC)方法来有效地搜索最优匹配。 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。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。Woodcock博士主要致力于开发和维护QM/MM接口，以及向现有的QM/MM副本/路径和微调弹性带(NEB)方法添加功能。最近的QM/MM增强向CHARMM添加了对从头算软件包Q-Chem的支持。我们还开发了一种路径采样技术，以降低计算成本来重现复杂化学/生化反应的平均作用力(PMF)势。

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 - Isotropic Periodic Sum method 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) - 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 lineal scaling methods for ab initio combined Quantum Mechanical/Molecular Modeling - Enhancements of QM/MM potentials (using 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 - Development of accurate interaction energy calculations for macromolecules - Development of a rapid search strategy for docking two macromolecules 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. 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. Dr. Woodcock has primary been focused on developing and maintaining QM/MM interfaces as well as adding functionality to the existing QM/MM Replica/Path and Nudged Elastic Band (NEB) methods. A recent QM/MM enhancement added support for the ab initio software package Q-Chem to CHARMM. We have also developed a pathway sampling techniques to reproduce the potential of mean force (PMF) of complex chemical/biochemical reactions with reduced computational costs.