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.

新的理论技术正在开发和表征。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求和利益驱动的。具体正在进行的项目包括： - 电子显微镜图像的约束分子动力学。 - 异质系统的扩展各向同性周期和方法 - 振动子系统分析 (VSA) 方法，用于将全局运动耦合到局部子系统，同时考虑环境的惯性效应。 - 扩展了 MSCALE 设施以支持 Hessian 评估 - QM/MM 扩展可有效支持移动块 Hessian (MBH) 方法 - 朗之万网络模型（LNM） - 基于扩展 TIGER 方法的新哈密顿副本交换方法 - Calpha 侧链模型 (C-SCM) 的粗粒度表示。 - 恒力副本交换 - 分子转移模型，可以准确预测蛋白质特性作为渗透剂类型和浓度以及 pH 的函数。 - 电子显微镜和断层扫描图像处理 - 开发电力密度图对接实用程序（EMAP） - 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采样和沿反应路径平均力潜力的估计 - 开发 REPLICA/PATH 方法，用于使用 Q-Chem 模拟退火确定复杂系统中的反应路径吴博士一直致力于利用电子显微镜图像开发约束分子动力学。开发了一种约束动力学算法，根据具有完全灵活的原子模型的电子显微镜图像来研究生物大分子系统的构象变化。通过合并图谱约束来模拟全原子大分子系统，以产生最合适的构象，并且轨迹为构象变化途径提供线索。这种方法充分利用了实验图像信息和分子动力学模拟的最新技术。该方法为协助蛋白质动态过程的多状态研究提供了有效的工具。吴博士还增强了各向同性周期和方法，使其适用于异质系统。基于3D IPS能够很好地描述局部区域大于异质尺度的异构系统的长程相互作用，本文提出了一种利用3D IPS计算各类仿真系统长程相互作用的方法，包括同构、异构和有限系统。该方法将长程相互作用分为两部分，短程部分和长程部分。短程部分是通过对截止范围（大约 10 ）内的原子对求和来计算的。远程部分使用快速傅里叶变换（FFT）技术来计算。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。示例模拟表明该方法可以准确有效地计算分子模拟的长程相互作用。 Woodcock 博士一直致力于开发一种新的振动子系统分析 (VSA) 方法，用于将全局运动耦合到局部子系统，同时考虑环境的惯性效应。 VSA 方法的前提是将系统划分为较小的感兴趣区域和通常称为环境的较大部分。该方法可以研究局部-全局耦合，更准确地估计大型系统各部分的振动自由能贡献，并消除弹性网络模型计算中的“尖端效应”。此外，VSA 方法还可用作可能导致自由能差异的特定自由度的探测 VSA 方法可以以多种方式使用，但它可能对估计 QM/MM 反应路径计算中的活化自由能最有用。 Woodcock 博士最近扩展了 MSCALE 工具（之前添加到 CHARMM 的通用多尺度建模功能）以支持正态模式分析。此扩展在可用解析二阶导数和必须进行数值计算的两种情况下（自动）起作用； CHARMM 是唯一具有此功能的软件包。 Woodcock 博士与 Yihan Shao 博士和 An Ghysels 女士（根特大学）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。通过减少 QM/MM Hessian 计算期间必须评估的自由度数量，此扩展使得研究以前计算要求过高的系统成为可能。量子力学/分子力学（QM/MM）技术对于酶机制中竞争反应途径的理论检验非常有用。 GAMESS-UK 已紧密集成到 CHARMM 中，以便研究小分子和酶复合物的催化路径。 Woodcock 博士主要致力于开发和维护 QM/MM 接口，以及向现有 QM/MM 副本/路径和微推弹性带 (NEB) 方法添加功能。 Miller先生主导开发了Langevin网络模型（LNM），该模型将弹性网络模型（ENM）与Lamm和Szabo开发的Langevin模式方法相结合。溶剂摩擦会影响生物大分子的行为，但标准简正模分析不包括这种力。通过将 Langevin 模式与粗粒度模型 (ENM) 相结合，LNM 可以捕获摩擦的影响，同时保持模拟足够小，以便在廉价的硬件上运行。该方法也已用于研究肌球蛋白 II 运动蛋白。 Itoh 博士开发了一种新的哈密顿复制品交换方法。该方法结合了标准哈密顿副本交换方法和克莱姆森大学合作者开发的 TIGER（全局能量重新分配温度区间）方法。尽管原始TIGER方法只能在温度空间进行有效采样，但其优点是可以在适当的反应坐标空间中实现有效采样。新方法的评估正在进行中。 O'Brien 先生进一步开发和扩展了用于模拟的蛋白质 Calpha 侧链模型 (C-SCM) 表示。 C-SCM 是一种粗粒度的蛋白质模型，其中氨基酸由两个相互作用位点（珠子）表示，一个位于蛋白质主链上的 C-α 碳位置，另一个位于蛋白质的质心。侧链，前提是氨基酸具有侧链。 C-SCM 非常强大，因为它允许有效地遍历模拟蛋白质折叠，并在单个轨迹中观察到许多折叠/展开转变。为了进一步增强采样，O'Brien 先生进一步开发了他的副本交换代码，以执行其他类型的副本交换并提高可用性。他的代码允许恒力复制品交换，可用于模拟单分子力实验，类似于在湿实验室中使用原子力显微镜或激光光学镊子所做的事情。 O'Brien 先生还开发了一个多功能软件包，该软件包实施加权直方图分析方法 (WHAM)，该方法根据分子模拟给出平衡蛋白质特性的最佳估计。该软件包包括分子转移模型的实现，可以根据渗透剂类型和浓度以及 pH 值准确预测蛋白质特性。

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.