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: 8746549
• 负责人: Bernard R Brooks
• 金额: $ 77.32万
• 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/8746549
• 关键词: Active Sites; Address; Affect; Alanine; Algorithms; Amber; Amyloid beta-Protein; Basic Science; Behavior; Benchmarking; Biochemical Pathway; Biochemical Reaction; Biological; Biological Process; Biophysics; Body Size; Catalysis; Cells; Cereals; Chemicals; Code; Complement; Computational Biology; Computational Technique; Computer Assisted; Computers; Computing Methodologies; Coupled; Development; Drug Design; Electron Microscopy; Enzymes; Evaluation; Exhibits; Free Energy; Freedom; Gene Expression Microarray Analysis; Generations; Goals; Height; Hemoglobin; Human; Hybrids; Image Analysis; Laboratories; Lead; Length; Ligands; Maps; Mechanics; Membrane Proteins; Methods; Micrococcal Nuclease; Modeling; Molecular; Molecular Conformation; Molecular Models; Names; National Heart, Lung, and Blood Institute; Noise; Peptides; Pharmacotherapy; Play; Potential Energy; Process; Protein Dynamics; Proteins; Psychological Techniques; Quantum Mechanics; Research; Research Project Grants; Role; Sampling; Science; Scientist; Simulate; Solvents; Staging; Structure; System; Techniques; Temperature; Testing; Therapeutic Intervention; Time; Variant; Viral Proteins; Water; base; biological systems; chemical group; computing resources; design; evaluation/testing; gene function; human EML2 protein; human disease; improved; interest; macromolecule; method development; models and simulation; molecular dynamics; molecular mechanics; molecular modeling; multi-scale modeling; novel; parallel architecture; particle; physical state; prevent; programs; protonation; quantum; research study; residence; simulation; small molecule; software development; therapy design/development; tool

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. Combining Hamiltonian and temperature based or SGLD based replica exchange methods. Hamiltonian replica exchange methods (H-REX) have been widely used to enhance conformational sampling of biomolecules. Generally, Hamiltonian exchange simulations have been performed with a constant temperature. Recently, we have implemented a new replica exchange code in CHARMM, which combines a Hamiltonian exchange method with a temperature exchange (TH-REX) and a self-guided Langevin dynamics (SGLD) exchange method (SGH-REX). In the new exchange methods, Hamiltonians and temperatures (TH-REX)/SGLD-guiding factors (SGH-REX) are exchanged simultaneously to enhance conformational sampling further. We have tested a new method with an alanine di-peptide and a beta-hairpin peptide in implicit water, and a beta-hairpin in explicit water condition. The benchmark results show that TH-REX and SGH-REX methods can successfully perform the Boltzmann sampling of conformations of biomolecules. In the implicit solvent condition, TH-REX and SGH-REX both enhance the sampling efficiency of H-REX. However, for the explicit water simulation, only SGH-REX can enhance the sampling efficiency because SGLD accelerates a conformational sampling without changing potential energy distributions. Introducing temperature exchange to H-REX of explicit water simulation shifts the potential energy distributions of replica and significantly lowers the exchange ratio of H-REX, which decreases the sampling efficiency of H-REX. These results suggest that a new SGH-REX can be a powerful tool for conformational sampling of biomolecules. Constant pH simulation using enveloping distribution sampling (EDS) method. Cellular pH is an important environmental variable, which can affect the structure and dynamics of proteins. Some proteins, such as viral proteins or human hemoglobin, depend on cellular pH to regulate their functions. Therefore, simulating the dynamics of biomolecules under a constant pH condition is one of the important problems in computational biophysics. However, in explicit water, the protonated and deprotonated states of titratable residues of biomolecules are separated by a large energy barrier, which prevents frequent transitions between states. To facilitate the transition between two states, we are developing a new constant pH simulation method using the enveloping distribution sampling (EDS) method. The EDS enables sampling of energetically separated states by performing molecular dynamics on a hybrid Hamiltonian, which envelops multiple states through non-physical states. The height of energy barrier of hybrid Hamiltonian can be controlled by a smoothing parameter. A low energy barrier can enhance transition but reduces the residence time of physical states. We are developing a new method based on a Hamiltonian exchange framework, where replicas are exchanged between hybrid Hamiltonians with different energy barriers and smoothness. By using this algorithm, we believe that frequent transitions between states and reasonable residence time in physical states can be accomplished simultaneously. Double reservoir pH replica exchange method. MD simulations at constant pH allow for the change in protonation states of ionizable groups during the course of a trajectory and are potentially an excellent tool for both a more realistic description of protein dynamics, and a calculation of pKa values of ionizable groups. In some cases constant pH simulations suffer from sampling issues. We have previously improved sampling in constant pH simulations by developing the pH replica exchange (pH-Rex) method. However, for some challenging cases, sampling still remained an issue. We have now developed the double reservoir pH replica exchange method (DR-pH-Rex) which relies on generation of two reservoirs of conformations at very low and very high pH values that correspond to the fully protonated and fully deprotonated states. When tested on a small peptide and on a challenging system, the V66K variant of Staphylococcal nuclease, the DR-pH-rex method exhibits improved conformational sampling as compared to the pH-Rex method, faster convergence and less noise in the calculated pKa values. Other replica exchange methods development. The lab has been heavily involved in the development of new replica exchange methods. We have combined reservoir replica exchange with the Conformation al Space Annealing method to produce a highly efficient sampling method that can accurately and quickly probe energy barriers between biologically relevant states of a protein system. This method has now been fully integrated into the CHARMM molecular simulation package. However, the use of reservoir methods is challenging because of issues with reservoir bias. A new method, Perturbed Reservoir Replica Exchange (P-RREX), is under development. The primary advantage of this method is that it does not make any assumption about the composition of the reservoir. Although sampling efficiency will be limited by reservoir quality, P-RREX will produce a Boltzmann ensemble using any reservoir. An early implementation of this method has been added to CHARMM and is currently being tested. Developing a hybrid quantum-chemical/molecular mechanical approach for free energy calculations. The reliability of free energy simulations is limited by two factors: a) the need for correct sampling and b) the accuracy of the parameters in classical molecular modeling. Parametrization is especially problematic in drug design, where ligands often contain non-standard chemical groups. On the other hand, parameter-free ab initio methods tend to be too computationally expensive for adequate sampling in biomolecular systems. A simple way to address this problem is by post-processing molecular dynamics simulations with quantum-chemical calculations. First, a molecular dynamics trajectory is generated to perform proper sampling of all relevant degrees of freedom. In a second step, the potential energies of each frame of the trajectory are evaluated with a quantum mechanics (QM) or quantum mechanics/molecular mechanics (QM/MM) approach. Free energy differences are then calculated based on the QM or QM/MM energies using the Non-Boltzmann Bennett (NBB) method. Since all energy evaluations of the post-processing stage are independent of each other, this approach is trivial to parallelize. Thus, highly parallel computer architectures can be employed with high efficiency, which allows us to perform the post-processing very rapidly. Novel Rigid Structure Dynamics Algorithm. The rigid body methods have wide range of applications in molecular dynamics (MD) simulations. The most widely implemented rigid body methods, SHAKE and RATTLE, apply bond length constraints in MD simulations with limitation on rigid body size. We developed a novel rigid body simulation algorithm, named SHAPE and implemented in CHARMM, to maintain rigid structures in Verlet based Cartesian MD simulations. This algorithm avoids the calculations of Lagrange multipliers, so that the complexity of computation does not increase with the number of particles in a rigid structure. Through this method, an arbitrary number of particles can be selected to form single rigid structure, and an arbitrary number of such rigid structures can be implemented in simulation. A unique feature of the SHAPE method is that it is interchangeable with SHAKE for any object that can be constrained as a rigid structure using multiple SHAKE constraints. Continuing development of Self Guided Langevin Dynamics (SGLD) continues.

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。 结合哈密顿量和基于温度或基于 SGLD 的副本交换方法。 哈密​​顿复制品交换方法（H-REX）已被广泛用于增强生物分子的构象采样。一般来说，哈密顿交换模拟是在恒定温度下进行的。最近，我们在 CHARMM 中实现了一种新的副本交换代码，它结合了带有温度交换的哈密顿交换方法（TH-REX）和自引导朗之万动力学（SGLD）交换方法（SGH-REX）。在新的交换方法中，哈密顿量和温度 (TH-REX)/SGLD 引导因子 (SGH-REX) 同时交换，以进一步增强构象采样。我们测试了一种新方法，在隐式水中使用丙氨酸二肽和 β-发夹肽，在显式水条件下使用 β-发夹。基准测试结果表明，TH-REX和SGH-REX方法可以成功地对生物分子构象进行玻尔兹曼采样。在隐式溶剂条件下，TH-REX和SGH-REX都提高了H-REX的采样效率。 然而，对于显式水模拟，只有 SGH-REX 可以提高采样效率，因为 SGLD 加速了构象采样而不改变势能分布。在显式水模拟的H-REX中引入温度交换会改变副本的势能分布，并显着降低H-REX的交换率，从而降低H-REX的采样效率。这些结果表明，新的 SGH-REX 可以成为生物分子构象采样的强大工具。 使用包络分布采样 (EDS) 方法进行恒定 pH 模拟。 细胞pH值是一个重要的环境变量，它可以影响蛋白质的结构和动力学。一些蛋白质，例如病毒蛋白或人类血红蛋白，依赖于细胞 pH 值来调节其功能。因此，模拟恒定pH条件下生物分子的动力学是计算生物物理学的重要问题之一。然而，在显性水中，生物分子可滴定残基的质子化和去质子化状态被大的能量势垒隔开，这阻止了状态之间的频繁转变。为了促进两种状态之间的转换，我们正在开发一种使用包络分布采样 (EDS) 方法的新的恒定 pH 模拟方法。 EDS 通过对混合哈密顿量执行分子动力学来实现能量分离状态的采样，该混合哈密顿量通过非物理状态包围多个状态。混合哈密顿量的能垒高度可以通过平滑参数来控制。低能垒可以增强转变，但会减少物理状态的停留时间。我们正在开发一种基于哈密顿交换框架的新方法，其中副本在具有不同能量势垒和平滑度的混合哈密顿量之间交换。通过使用该算法，我们相信可以同时完成状态之间的频繁转换和物理状态的合理停留时间。 双池pH复制品交换法。 恒定 pH 下的 MD 模拟允许在轨迹过程中可电离基团的质子化状态发生变化，并且可能是更真实地描述蛋白质动力学和计算可电离基团的 pKa 值的绝佳工具。在某些情况下，恒定 pH 模拟会遇到采样问题。我们之前通过开发 pH 副本交换 (pH-Rex) 方法改进了恒定 pH 模拟中的采样。然而，对于一些具有挑战性的案例，采样仍然是一个问题。我们现在开发了双库 pH 复制品交换方法 (DR-pH-Rex)，该方法依赖于在非常低和非常高的 pH 值下生成两个构象库，对应于完全质子化和完全去质子化状态。当在小肽和具有挑战性的系统（葡萄球菌核酸酶的 V66K 变体）上进行测试时，与 pH-Rex 方法相比，DR-pH-rex 方法表现出改进的构象采样、更快的收敛速度以及计算的 pKa 值中的噪音更少。 其他副本交换方法的开发。 该实验室积极参与新副本交换方法的开发。我们将储库复制品交换与构象空间退火方法相结合，产生了一种高效的采样方法，可以准确、快速地探测蛋白质系统的生物学相关状态之间的能量势垒。该方法现已完全集成到 CHARMM 分子模拟软件包中。然而，由于储层偏差问题，储层方法的使用具有挑战性。一种新方法——扰动储层副本交换（P-RREX）正在开发中。该方法的主要优点是它不对储层的成分做出任何假设。尽管采样效率会受到储层质量的限制，但 P-RREX 将使用任何储层生成玻尔兹曼系综。此方法的早期实现已添加到 CHARMM 中，目前正在测试中。 开发用于自由能计算的混合量子化学/分子力学方法。 自由能模拟的可靠性受到两个因素的限制：a）正确采样的需要；b）经典分子建模中参数的准确性。参数化在药物设计中尤其成问题，其中配体通常包含非标准化学基团。另一方面，无参数从头开始方法 对于生物分子系统中的充分采样来说，计算成本往往太高。解决这个问题的一个简单方法是通过量子化学计算对分子动力学模拟进行后处理。首先，生成分子动力学轨迹以对所有相关自由度进行适当的采样。第二步，使用量子力学 (QM) 或量子力学/分子力学 (QM/MM) 方法评估轨迹每一帧的势能。然后使用非玻尔兹曼贝内特 (NBB) 方法根据 QM 或 QM/MM 能量计算自由能差。由于后处理阶段的所有能量评估都是相互独立的，因此这种方法很容易并行化。因此，可以高效地采用高度并行的计算机架构，这使我们能够非常快速地执行后处理。 新颖的刚性结构动力学算法。 刚体方法在分子动力学（MD）模拟中具有广泛的应用。最广泛实施的刚体方法 SHAKE 和 RATTLE 在 MD 模拟中应用键长约束，并限制刚体尺寸。我们开发了一种新颖的刚体模拟算法，名为 SHAPE，并在 CHARMM 中实现，以在基于 Verlet 的笛卡尔 MD 模拟中保持刚性结构。 该算法避免了拉格朗日乘子的计算，使得计算复杂度不会随着刚性结构中粒子数量的增加而增加。通过该方法，可以选择任意数量的粒子来形成单个刚性结构，并且可以在模拟中实现任意数量的这种刚性结构。 SHAPE 方法的一个独特功能是，对于可以使用多个 SHAKE 约束将其约束为刚性结构的任何对象，它可以与 SHAKE 互换。 自引导朗之万动力 (SGLD) 的持续开发仍在继续。