Next Generation Forcefield for Internal Coordinate Mechanics

下一代内坐标力学力场

基本信息

批准号：
7612513
负责人：
Maxim Totrov
金额：
$ 10万
依托单位：
MOLSOFT, LLC
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-02-15 至 2010-02-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7612513
关键词：
Amino Acids Aphorisms Area Attention Benchmarking Biological Process Boundary Elements Cations Code Complex Computational Biology Computer Assisted Computer Simulation Computer software DNA Development Disease Docking Doctor of Philosophy Foundations Freezing Goals Heart Hydrogen Bonding Ions Libraries Ligands Literature Mechanics Metalloproteins Metals Methods Modeling Modification Molecular Molecular Conformation Molecular Models Molecular Structure Output Peptides Performance Phase Physics Potential Energy Protein Analysis Proteins Protocols documentation Publications Publishing Relative (related person)Research Personnel Rotation Screening procedure Set protein Space Models Staging Structural Biologist Structure Surface Techniques Testing Torsion Universities Validation Work Writing base drug discovery flexibility graphical user interface improved molecular mechanics molecular modeling next generation performance tests polypeptide programs protein structure prediction public health relevance simulation small molecule success tool virtual

项目摘要

DESCRIPTION (provided by applicant): Molecular modeling using internal coordinates, rather than more traditional Cartesian approaches, is gaining recognition because of its significant computational efficiency advantages. Molsoft's ICM (Internal Coordinate Mechanics) is among the very few molecular modeling programs built from the ground up using internal coordinates. ICM is probably the only such software program with the breadth of application fields including protein structure prediction, peptide and ligand conformational analysis, protein/protein and protein/ligand docking and virtual screening. In any molecular mechanics application, the accuracy of the force-field is the foundation for successful modeling. Working in internal coordinates, in particular torsions, imposes specific requirements on the force-fields used in the simulations. Indeed, when Cartesian force-field energy is (mis)used to evaluate conformations generated in torsion space (with the covalent geometry frozen), large errors in the relative energies of energy minima as well as rotation barriers are inevitable because the Cartesian force-field parameters are optimized on structures with relaxed covalent geometry. The ECEPP05 force-field recently developed and published by Prof. Harold Scheraga's group at Cornell University represents a major step forward in the development of torsion space force-fields. Importantly, solvation parameters specifically derived to work in conjunction with other non-bonded and bonded terms were also developed and are in the late stages of publication. Phase I of this project will focus on the implementation and integration of ECEPP05 into the ICM platform. At the end of Phase I, we expect to have a release of ICM that will allow users to apply the new force-field in their protein simulations. We will further test the performance of the new force-field in loop modeling. We already have a Monte-Carlo minimization-based loop simulation protocol implemented in ICM. This protocol showed promising results in internal benchmarking, and we expect to achieve higher accuracy in this important class of polypeptide simulations using the new force-field. The long term (Phase II) goal of this proposal is to further expand ECEPP05 into a general-purpose force-field that could be applied to small molecules and in particular in docking. Other extensions will include parameters for DNA and metalloprotein modeling. PUBLIC HEALTH RELEVANCE: Molecular mechanics techniques increasingly allow in-silico simulation of essential biological processes at the atomic level. Molsoft's ICM (Internal Coordinate Mechanics) software platform is a particularly efficient modeling tool because of its use of internal variables, rather than traditional Cartesian coordinates, in the description of the molecular structure. ICM is increasingly used by researchers in various structural and computational biology projects, including computer-assisted drug discovery. The force-fields that quantitatively describe atomic interactions are at the heart of molecular mechanics modeling, and the accuracy of molecular simulation can only be as good as the underlying force-fields. Equipping structural biologists with the latest ECEPP05 force-field from Cornell University, together with its further improvements at Molsoft, will help bring molecular simulations and structure predictions to the next level of accuracy. Successful structure modeling will ultimately help improve our understanding of molecular mechanisms underlying disease and help accelerate structure-based drug discovery efforts.

描述（由申请人提供）：使用内部坐标而不是更传统的笛卡尔方法进行分子建模，因为其具有显着的计算效率优势，因此获得了识别。 Molsoft的ICM（内部坐标力学）是使用内部坐标从头开始构建的极少数分子建模程序之一。 ICM可能是唯一具有应用程序广度的软件程序，包括蛋白质结构预测，肽和配体构象分析，蛋白质/蛋白质和蛋白质/配体对接和虚拟筛查。在任何分子力学应用中，力场的准确性是成功建模的基础。在内部坐标中工作，特别是扭转，对模拟中使用的力场施加了特定要求。实际上，当用于评估扭转空间中产生的构象（随着共价几何形状而冻结）时（MIS）时，能量最小值的相对能量以及旋转屏障的相对能量的较大误差是不可避免的，因为卡车式力量野外参数是在宽松的协调相关图的结构上优化的。 ECEPP05 Force-Field最近由Harold Scheraga教授在康奈尔大学（Cornell University）的小组开发和出版，这代表了扭力太空力量场发展的重要一步。重要的是，也开发了专门得出的溶剂化参数，该参数与其他非键合和键合项结合使用，并且处于出版的晚期。该项目的第一阶段将集中于ECEPP05进入ICM平台的实施和集成。在第一阶段结束时，我们预计将发布ICM，该版本将允许用户在其蛋白质模拟中应用新的力场。我们将进一步测试循环建模中新力场的性能。我们已经在ICM中实现了基于蒙特卡洛最小化的循环仿真协议。该协议在内部基准测试中显示出令人鼓舞的结果，我们希望使用新的力场在这一重要类别的多肽模拟中获得更高的准确性。该提案的长期目标（II期）目标是将ECEPP05进一步扩展到可以应用于小分子的通用力场，尤其是在对接中。其他扩展将包括用于DNA和金属蛋白建模的参数。公共卫生相关性：分子力学技术越来越多地允许在原子水平上对基本生物过程进行模拟。 Molsoft的ICM（内部坐标力学）软件平台是一种特别有效的建模工具，因为它在分子结构的描述中使用了内部变量而不是传统的笛卡尔坐标。 ICM越来越多地被各种结构和计算生物学项目（包括计算机辅助的药物发现）中使用。定量描述原子相互作用的力场是分子力学建模的核心，而分子模拟的准确性只能与基础力场一样好。为结构生物学家配备了康奈尔大学最新的ECEPP05力场，并在Molsoft进行了进一步的改进，将有助于将分子模拟和结构预测带入更高的准确性。成功的结构建模最终将有助于提高我们对疾病潜在的分子机制的理解，并有助于加速基于结构的药物发现工作。