DEVELOPMENT OF THEORETICAL METHODS FOR STUDYING BIOLOGICAL MACROMOLECULES

生物大分子研究理论方法的发展

• 批准号: 6290394
• 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/6290394
• 关键词: chemical models; computer program /software; computer simulation; computer system design /evaluation; macromolecule; method development; molecular dynamics; quantum chemistry

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 projects include: - Enhancements in the development of Particle Mesh Ewald (PME) methods - Evaluation of Ewald summation net-charge corrections (PME) - Calculating free energies with Ewald methods in net-charged systems - Use of a FFT filter function with PME for rapid evaluation of electrostatics interactions for finite systems - Minimal explicit ion problem for periodic systems- 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 - Calculation of pK of acids groups using Free Energy Perturbation and PME corrections.- Development of improved integration techniques for molecular dynamics - Development of flexible MD techniques that remove high frequency degrees of freedom - Development of a non-reversible RESPA integrator for improved molecular dynamics simulations using a multiple timestep - Evaluation of Locally Enhanced Sampling (LES) for conformational searching - New constraint integrator; rigid bodies, massless lone pairs, and others- Other method development - Development of RMS best-fit restraints; accurate forces, relative restraints - Rational drug design: shape descriptor facility for CHARMM - Development of accurate interaction energy calculations for macromolecules - Evaluation of small molecule/protein binding energy prediction methods - Development of a rapid search strategy for docking two macromolecules There has been a significant effort in improving the techniques used to model complex systems with a mixture of quantum mechanics (QM) and classical mechanics (MM). QM/MM methods offer the possibility of treating a region of interest within a biological system quantum mechanically thereby allowing the accurate representation of bond breaking, formation, and electron transfer while also including important structural and charge effects from a surrounding classical region. 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) and graphic capabilities not available in either the current GAMESS, MOPAC, or CADPAC interfaces. 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. The interface has been tested on small molecules which are often pathological cases for the single- and double-link atom methods. Although many of the parameter sets and models that are generally available are of the quality required for accurate simulation of macromolecular systems, there remains the need to weigh the relative merits of these sets for the specific types of systems studied. Ongoing projects include: - Evaluation and improvement of current state of the art DNA force fields - Evaluation of protein parameter sets - Evaluation of CVFF, MMFF (Merck), and other nonstandard force fields - Development and use of a polarizable and flexible water model - molecular dynamics, simulation, theory, molecular graphics, quantum mechanics, CHARMM

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。具体项目包括：- 增强粒子网格埃瓦尔德（PME）方法的开发-埃瓦尔德求和净电荷校正（PME）的评估-在净电荷系统中使用埃瓦尔德方法计算自由能-使用FFT滤波器功能和PME快速评估有限系统的静电相互作用-周期系统的最小显式离子问题-研究复杂系统中反应机制的方法。- 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的估计-使用模拟退火确定复杂系统中反应途径的REPLICA/PATH方法的开发-联合量子力学/分子建模（QM/MM）势的开发（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-使用双键原子接口的密度泛函QM/MM-QM/MM界面交替处理的评估-使用自由能扰动和PME校正计算酸基团的pK。发展改进的分子动力学积分技术--发展去除高频自由度的灵活的MD技术--发展一种使用多时间步的改进的分子动力学模拟的不可逆的EMAA积分器--评价用于构象搜索的局部增强取样（LES）--新的约束积分器;刚体、无质量孤对电子和其他.其他方法的开发. RMS最佳配合约束的开发;精确力、相对约束.合理药物设计：CHARMM的形状描述符设施.大分子精确相互作用能计算的发展.小分子/蛋白质结合能预测方法的评价对接两个大分子的快速搜索策略的发展在改进用于用量子力学（QM）和经典力学（MM）的混合来模拟复杂系统的技术方面已经做出了重大努力。QM/MM方法提供了在生物系统内量子力学地处理感兴趣区域的可能性，从而允许精确表示键断裂、形成和电子转移，同时还包括来自周围经典区域的重要结构和电荷效应。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提供了当前GAMESS、MOPAC或CADPAC接口中不具备的DFT（密度泛函理论）和图形功能。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。该接口已在小分子上进行了测试，这些小分子通常是单链接和双链接原子方法的病理情况。尽管许多通常可用的参数集和模型具有准确模拟大分子系统所需的质量，但仍然需要权衡这些参数集对于所研究的特定类型系统的相对优点。正在进行的项目包括：- 评估和改进现有技术的DNA力场-评估蛋白质参数集-评估CVFF、MMFF（Merck）和其他非标准力场-开发和使用可极化和灵活的水模型-分子动力学、模拟、理论、分子图形学、量子力学、CHARMM