Development Of Theoretical Methods For Studying Biologic

生物学研究理论方法的发展

• 批准号: 6546757
• 负责人: BERNARD R BROOKS
• 金额: --
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6546757
• 关键词: chemical models; computer program /software; computer simulation; computer system design /evaluation; dipole moment; macromolecule; method development; model design /development; molecular dynamics; quantum chemistry; solutions; structural biology

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.

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： - 开发了电密度图对接工具，为电密度图实验研究提供了有效的工具。 - 完善蛋白质结构预测探索，探索蛋白质结构预测的信息化途径。 - 复杂体系反应机理研究方法的发展。 - 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 - 合理的药物设计：CHARMM的形状描述工具-开发精确的大分子相互作用能计算 - 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。 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。该实验室已经开发出“双链接原子与高斯 模糊（DLA/DGMM）技术。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合能。结果表明，我们的方法和实现分区的分子到量子和分子力学区域是强大的，将是非常有帮助的研究酶的机制。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提供了DFT（密度泛函理论）。经典部分电荷的高斯卷积（模糊）已经实现和测试。这些离域电荷减少了伪影，并改善了用于处理QM/MM边界条件的双链接原子方法。 与Toshiko Ichiye教授合作，努力改进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。