DEVELOPMENT OF THEORETICAL METHODS FOR STUDYING BIOLOGICAL MACROMOLECULES

新的理论技术正在发展和形成特点。这些工作通常与软件开发相结合，并涉及对新想法的系统测试和评估。这种发展是由当前的需要和利益驱动的。具体项目包括：-改进粒子网格埃瓦尔德（PME）方法的发展-评估埃瓦尔德求和净电荷修正(PME) -在净带电系统中使用埃瓦尔德方法计算自由能-使用FFT滤波函数与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-开发检查复杂系统中反应机理的方法。-复杂构象转变的无偏强制抽样和沿反应路径平均力势的估计-开发用于使用模拟退火确定复杂系统中反应路径的REPLICA/PATH方法-开发量子力学/分子建模（QM/MM）联合电位（高斯离域MM电荷），QM/MM应用的GAMESS-UK和CHARMM集成-使用双键原子界面的密度函数QM/MM - QM/MM界面的替代处理的评估-使用自由能微扰和PME校正计算酸群的pK。-开发改进的分子动力学积分技术-开发灵活的MD技术，消除高频自由度-开发不可逆的RESPA积分器，用于改进使用多时间步长的分子动力学模拟-评估用于构象搜索的局部增强采样(LES) -新的约束积分器；刚体、无质量孤对和其他。其他方法开发。RMS最适合约束的开发；精确的力，相对约束-合理的药物设计：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估-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）混合建模复杂系统的技术方面已经做出了重大努力。QM/MM方法提供了量子力学处理生物系统中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已紧密集成到CHARMM中，以允许研究小分子和酶复合物的催化途径。这扩展了CHARMM中的QM/MM套件，因为GAMESS- uk提供了DFT（密度泛函数理论）和图形功能，这些功能在当前的GAMESS、MOPAC或CADPAC接口中都是不可用的。高斯卷积（模糊）的经典部分电荷已经实现和测试。这些离域电荷减少了伪影，并改进了处理QM/MM边界条件的双链接原子方法。该界面已在小分子上进行了测试，这些小分子通常是单键和双键原子方法的病理病例。虽然许多通常可用的参数集和模型具有精确模拟大分子系统所需的质量，但仍然需要对所研究的特定类型系统的这些集的相对优点进行权衡。正在进行的项目包括：-评估和改进当前最先进的DNA力场-评估蛋白质参数集-评估CVFF， MMFF（默克）和其他非标准力场-开发和使用极化和柔性水模型-分子动力学，模拟，理论，分子图形，量子力学，CHARMM

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