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，为电子密度图实验研究提供有效工具。 -细化蛋白质结构预测探索，探索预测蛋白质结构的信息化方法。 -开发研究复杂体系中的反应机理的方法。 -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 -合理的药物设计：CHARMM的形状描述工具-开发大分子的精确相互作用能计算 -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。 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。实验室已经研制出了高斯型双键原子 模糊(DLA/DGMM)技术。我们计算了一系列模型化合物的转动势垒、去质子化能和质子亲和能。结果表明，我们将分子划分为量子力学和分子力学区域的方法和实现是稳健的，将对研究酶的机制非常有帮助。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(密度泛函理论)。对经典部分电荷的高斯卷积(模糊)进行了实现和测试。这些离域电荷减少了伪影，改进了处理QM/MM边界条件的双链原子方法。 与Ichiye教授合作，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准确地进行生物分子的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: - Develop electric density map docking utility, provide a efficient tool for electric density map experimental studies. - Refine protein structure prediction exploration, Explore informational approach to predict 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 - Rational drug design: shape descriptor facility for CHARMM - 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. 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. We have computed the rotational barriers, deprotonation energies and proton affinities of a series of model compounds. The results indicate that our method and implementation of partitioning a molecule into quantum and molecular mechanics regions is robust and would be extremely helpful in 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 (Density Functional Theory). Gaussian convolution (blurring) of classical partial charges has been implemented and tested. These delocalized charges reduce artifacts and improve on the double link atom methodology for treating QM/MM boundary conditions. In collaboration with Prof. Toshiko Ichiye, there is an 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.