Development Of Theoretical Methods For Studying Biological Macromolecules

生物大分子研究理论方法的发展

基本信息

批准号：
7734954
负责人：
Bernard R Brooks
金额：
$ 74.12万
依托单位：
NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
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/7734954
关键词：
Affect Algorithms Amber Amino Acids Arts Atomic Force Microscopy Basic Science Behavior Binding Biological Biological Process Biophysics Blood Carbon Cereals Classification Code Collaborations Complement Complex Computational Biology Computational Technique Computer software Computers Computing Methodologies Coupled Coupling Development Docking Electron Microscopy Electrostatics Environment Equilibrium Evaluation Fourier Transform Free Energy Freedom Friction Gene Expression Goals Heart Heterogeneity Image Image Analysis Institutes Investigation Laboratories Lasers Lead Lung Maps Mechanics Methodology Methods Modeling Molecular Molecular Conformation Motion Motor Multienzyme Complexes Myosin Type II Numbers Pathway interactions Pharmacotherapy Play Positioning Attribute Process Property Protein Dynamics Proteins Psychological Techniques Publishing Range Reaction Research Research Project Grants Role Running Sampling Science Scientist Side Simulate Site Solvents Standards of Weights and Measures Structure Sum System Techniques Temperature Testing Universities Vertebral column Weight Work base conformational conversion density enzyme mechanism evaluation/testing image processing improved interest laser tweezer macromolecule method development models and simulation molecular dynamics molecular mechanics molecular modeling multi-scale modeling network models programs protein folding quantum research study simulation single molecule small molecule software development therapy design/development tomography tool usability

项目摘要

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: - Constrained Molecular dynamics with electron microscopy images. - Extended Isotropic Periodic Sum Method for Heterogeneous Systems - vibrational subsystem analysis (VSA) method for coupling global motion to a local subsystem while including the inertial effects of the environment. - Extended the MSCALE facility to support Hessian evaluations - QM/MM extensions to efficiently support mobile block Hessian (MBH) methodology - Langevin Network Model (LNM) - New Hamiltonian replica-exchange method based on extending the TIGER method - Calpha-Side Chain Model (C-SCM) coarse grained representation of. - constant-force replica exchange - Molecular Transfer Model, which allows for the accurate prediction of protein properties as a function of osmolyte type and concentration, and pH. - Electron Microscopy and Tomography Image Processing - Development of electric density map docking utility (EMAP) - 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 with Q-Chem Dr. Wu has been developing constrained Molecular dynamics with electron microscopy images. A constraint dynamics algorithm is developed to study conformational change of biological macromolecular systems according to electron microscopy images with fully flexible atomic models. All-atom macromolecular systems are simulated with incorporated map constraint to produce best fitting conformations and the trajectories provide clues for conformational change pathways. This approach makes full use of experimental image information and state of art of molecular dynamics simulations. This method provide to efficient tool to assist multiple state study of protein dynamic processes. Dr. Wu has also enhanced the Isotropic Periodic Sum Method so that is works well for Heterogeneous Systems. Based on the fact that 3D IPS can well describe the long-range interactions of a heterogeneous system with a local region larger than the heterogeneity scale, this work presents a method to use 3D IPS to calculate long range interactions for all kinds of simulation systems, including homogeneous, heterogeneous, and finite systems. This method splits long range interactions into two parts, a short-range part and a long-range part. The short-range part is calculated by summing over atom pairs within a cutoff range (about 10 ). The long-range part is calculated using the fast Fourier transform (FFT) technique. This method is applied to electrostatic and vdw interactions for both periodic and none-periodic systems. Example simulations demonstrate this method can accurately and efficiently calculate long range interactions for molecular simulation. Dr. Woodcock has been working on the development of a new vibrational subsystem analysis (VSA) method for coupling global motion to a local subsystem while including the inertial effects of the environment. The premise of the VSA method is a partitioning of a system into a smaller region of interest and a usually larger part referred to as environment. This method allows the investigation of local-global coupling, a more accurate estimation of vibrational free energy contribution for parts of a large system, and the elimination of the tip effect" in elastic network model calculations. Additionally, the VSA method can be used as a probe of specific degrees of freedom that may contribute to free energy differences. The VSA approach can be employed in many ways, but it will likely be most useful for estimating activation free energies in QM/MM reaction path calculations. Dr. Woodcock has recently extended the MSCALE facility (general multiscale modeling functionality previously added to CHARMM) to support normal mode analysis. This extension works (automatically) in both cases where analytic second derivatives are available and where these have to be computed numerically; CHARMM is the only package that has this functionality. Dr. Woodcock in collaboration with Dr. Yihan Shao and Ms. An Ghysels (Ghent University) have been working on the implementation and testing of a QM/MM extension to the previously published mobile block Hessian (MBH) methodology. This extension makes it possible to study systems that were previously too computationally demanding by reducing the number of degrees of freedom that have to be evaluated during the QM/MM Hessian calculation. Quantum mechanical/molecular mechanical (QM/MM) techniques are extremely useful in the theoretical examination of competing reaction pathways in enzyme mechanisms. GAMESS-UK has been tightly integrated into CHARMM to allow studies of catalytic paths in small molecules and enzyme complexes. Dr. Woodcock has primary been focused on developing and maintaining QM/MM interfaces as well as adding functionality to the existing QM/MM Replica/Path and Nudged Elastic Band (NEB) methods. Mr. Miller has taken the lead in developing the Langevin Network Model (LNM) that combines the Elastic Network Model (ENM) with the Langevin Mode method developed by Lamm and Szabo. Solvent friction can affect the behavior of biological macromolecules, but this force is not included by standard normal mode analysis. By combining Langevin modes with a coarse grained model (ENM), the LNM captures the effect of friction while keeping simulations small enough to be run on inexpensive hardware. This method has also been used to study the protein myosin II motor protein. Dr. Itoh has developed a new Hamiltonian replica-exchange method. This method is a combination of the standard Hamiltonian replica-exchange method and the TIGER (Temperature Intervals with Global Energy Reassignment) method that was developed by collaborators at Clemson University. It has the advantage that effective samplings can be realized in appropriate reaction-coordinate space, although the original TIGER method can sample effectively the temperature space. Evaluation of the new method is ongoing. Mr. O'Brien has further developed and extended the Calpha-Side Chain Model (C-SCM) representation of proteins for simulations. The C-SCM is a coarse-grained model for proteins in which amino acids are represented with two interaction sites (beads), one located at the C-alpha carbon position on the protein backbone and one located at the center-of-mass of the side chain provided the amino acid has a side chain. The C-SCM is powerful because it allows effectively ergodic simulations of protein folding to be carried with many folding/unfolding transitions observed in a single trajectory. To further enhance sampling, Mr. O'Brien has further developed his replica exchange code to carry out additional types of replica exchange and improve usability. His code allows constant-force replica exchange useful for simulating single-molecule force experiments, analogous to what is done in wet labs using Atomic Force Microscopy or Laser Optical Tweezers. Mr. O'Brien has also developed a versatile software package that implements the Weighted Histogram Analysis Method (WHAM) which gives optimal estimates of equilibrium protein properties based on molecular simulations. This package includes an implementation of the Molecular Transfer Model, which allows for the accurate prediction of protein properties as a function of osmolyte type and concentration, and pH.

正在开发和表征新的理论技术。这些努力通常与软件开发相结合，涉及对新想法的系统测试和评估。这种发展是由当前的需求和利益驱动的。正在进行的特定项目包括： - 通过电子显微镜图像受约束的分子动力学。 - 异质系统的扩展各向同性周期性总和法 - 将全局运动耦合到本地子系统的振动子系统分析（VSA）方法，同时包括环境的惯性效应。 - 扩展了MSCALE设施以支持Hessian评估 -QM/MM扩展以有效支持移动块Hessian（MBH）方法 -Langevin网络模型（LNM） - 基于扩展老虎法的新型汉密尔顿复制品 - 交换方法 -Calpha侧链模型（C-SCM）粗粒表示。 - 恒定副本交换 - 分子转移模型，它允许准确预测蛋白质特性，这是渗透质类型和浓度以及pH的函数。 - 电子显微镜和断层扫描图像处理 - 电密度图对接实用程序（EMAP）的开发 - 开发用于检查复杂系统中反应机制的方法 - 复杂构象转变的强迫采样和沿反应途径的平均力潜力的估计 - 开发使用Q Chem模拟退火来确定复杂系统中反应路径的复制/路径方法 WU博士一直在使用电子显微镜图像开发约束的分子动力学。根据具有完全柔性原子模型的电子显微镜图像，开发了一种约束动力学算法来研究生物大分子系统的构象变化。使用合并的地图约束来模拟全原子大分子系统，以产生最佳拟合构象，轨迹为构象变化途径提供了线索。这种方法充分利用了实验图像信息和分子动力学模拟的艺术状态。该方法为有效的工具提供了有助于蛋白质动态过程的多种状态研究。 Wu博士还增强了各向同性的周期性方法，因此对异质系统非常有效。基于3D IP可以很好地描述具有大于异质性量表的局部区域的异质系统的远距离相互作用，这项工作提出了一种使用3D IP来计算各种模拟系统的远距离相互作用的方法，包括均质，异构性，异构性和实践系统。该方法将远距离相互作用分为两个部分，一个短距离部分和一个远距离部分。短距离部分是通过将原子对求和在截止范围内的（约10）来计算的。使用快速傅立叶变换（FFT）技术计算远程部分。该方法适用于周期性和非周期性系统的静电和VDW相互作用。示例模拟证明了此方法可以准确有效地计算分子模拟的远距离相互作用。 Woodcock博士一直致力于开发新的振动子系统分析（VSA）方法，以将全球运动耦合到本地子系统，同时包括环境的惯性效应。 VSA方法的前提是将系统分配到较小的感兴趣区域，通常称为环境。该方法允许研究本地全球耦合，更准确地估算大型系统部分的振动自由能贡献，以及消除“在弹性网络模型计算中”的尖端效应。此外，VSA方法可用于探测特定自由度的探测，可能会导致能量差异的特定自由度。 QM/mm反应路径计算。 Woodcock博士最近扩展了MSCALE设施（以前添加到CHARMM的一般多尺度建模功能），以支持正常模式分析。在两种情况下，该扩展名（自动）起作用，在两种情况下都可以使用分析性的第二个衍生物以及必须以数值计算这些衍生物； charmm是唯一具有此功能的软件包。 Woodcock博士与Yihan Shao博士和An Ghysels（Ghent University）合作，一直致力于对先前发布的移动块Hessian（MBH）方法进行QM/MM扩展的实施和测试。这一扩展使得通过减少在QM/mm Hessian计算过程中必须评估的自由度数量来研究以前过于计算要求的系统。量子机械/分子机械（QM/mm）技术在酶机制中竞争反应途径的理论检查中非常有用。 Gamess-UK已被紧密整合到CHARMM中，以允许研究小分子和酶复合物中的催化路径。 Woodcock博士主要专注于开发和维护QM/MM界面，并为现有的QM/MM副本/路径和裸弹性带（NEB）方法添加功能。米勒先生在开发Langevin网络模型（LNM）方面领先，该模型将弹性网络模型（ENM）与LAMM和Szabo开发的Langevin Mode方法相结合。溶剂摩擦会影响生物大分子的行为，但标准正常模式分析不包括这种力。通过将Langevin模式与粗粒子模型（ENM）相结合，LNM捕获了摩擦的效果，同时使模拟足够小，以便在廉价的硬件上运行。该方法还用于研究蛋白质肌球蛋白II运动蛋白。 Itoh博士开发了一种新的Hamiltonian副本 - 交换方法。这种方法是由克莱姆森大学合作者开发的标准汉密尔顿复制方法和老虎（具有全球能量重新分配）方法的老虎（具有全球能量重新分配）方法的组合。它具有一个优势，即可以在适当的反应坐标空间中实现有效采样，尽管原始的老虎方法可以有效地采样温度空间。对新方法的评估正在进行中。 O'Brien先生进一步开发并扩展了蛋白质的Calpha端链模型（C-SCM）表示模拟。 C-SCM是蛋白质的粗粒粒模型，其中氨基酸用两个相互作用位点（珠子）表示，一个位于蛋白质主链的C-α碳位置，另一种位于侧链的中心，前提是氨基酸具有侧链。 C-SCM具有强大的功能，因为它允许在单个轨迹中观察到的许多折叠/展开过渡有效地携带蛋白质折叠的模拟。为了进一步增强抽样，奥布莱恩先生进一步开发了他的复制交换法规，以进行其他类型的复制交换并提高可用性。他的代码允许恒定副本交换用于模拟单分子力实验，这类似于使用原子力显微镜或激光光学镊子在湿实验室中所做的事情。 O'Brien先生还开发了一个多功能软件包，该软件包实现了加权直方图分析方法（WHAM），该软件包基于分子模拟提供了最佳的平衡蛋白质估计。该软件包包括分子转移模型的实现，该模型允许准确预测蛋白质特性是渗透液类型和浓度以及pH的函数。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Langevin network model of myosin.

肌球蛋白的 Langevin 网络模型。

DOI：
10.1021/jp077042v
发表时间：
2008
期刊：
The journal of physical chemistry. B
影响因子：
0
作者：
Miller,BenjaminT;Zheng,Wenjun;Venable,RichardM;Pastor,RichardW;Brooks,BernardR
通讯作者：
Brooks,BernardR

Normal-modes-based prediction of protein conformational changes guided by distance constraints.