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: 8557904
• 负责人: Bernard R Brooks
• 金额: $ 61.14万
• 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/8557904
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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. 1. Improved self-guided molecular dynamics (SGLD) simulation methods for ensemble sampling Self-guided molecular dynamics Langevin dynamics was developed for enhanced conformational search. This method makes rare events that otherwise not accessible by regular dynamics simulation observable with current available computing resources. Typical applications include protein folding, signal transaction, water penetration, etc. A major challenge when applying the original SGLD method in simulation studies is how to quantitatively measure the ensemble deviation and how to correct the SGLD results. By analyzing the characteristics of the guiding force and SGMD/SGLD simulation behavior, we derived a thermodynamic relation between a regular simulation and a self-guided simulation. By separating low frequency part from high frequency part in a property, we are able to quantitative describe the enhancement in low frequency motion and correct for the alteration of the conformational distribution. This thermodynamic relation paves the way for many application and extension of the SGMD/SGLD methods. One immediate extension is by introducing the relation into the equation of motion, we developed the SGMDfp/SGLDfp method that can produce directly a correct conformational distribution while enhancing the conformational search. Another application is to combine SGLD with replica exchange with or without temperature increases. The advantage of SGLD-replica exchange without temperature change is that a reduced number of replica needed for large systems, such as a solvated protein. 2. Isotropic Periodic Sum Method for multipole interactions Multipole interactions play an important role in biological systems and increasing amount of effort have been contributed to include multipole interactions in force field development. The computation expense of multipole interactions are overwhelming for simulation. IPS method provides a convenient approach to tackle this problem. Based on IPS concept, we developed IPS potentials for multipole interactions. As a result, multipole interaction calculation can be carried out exactly as the cutoff method, with the IPS potentials as the switching function to account for long range contributions. 3. A novel rigid structure dynamics algorithm, SHAPE Rigid body methods have wide range of applications in molecular dynamics (MD) simulations. The most widely implemented rigid body methods, SHAKE and RATTLE, apply only bond length constraints in MD simulations with limitation on rigid body size. We presented a novel rigid body simulation algorithm, named SHAPE, 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. Numerical tests with four model systems including two proteins demonstrate that the accuracy and reliability of the SHAPE method are comparable to the SHAKE method, but with much more applicability and efficiency. 4. A novel algorithm for free energy method along reaction paths through rigid body simulation Estimation of reaction free energy with multiple reaction coordinates (RCs), especially enzymatic reactions, is a very active topic in computational chemistry and biology. We developed a highly efficient novel algorithm sampling the ffree energy along a reference reaction path with constraints on multiple Rcs. In this method, all the key atoms defining RCs can be selected to form a rigid structure using our SHAPE rigid body method as constraints during simulations. Through a series of MD simulations with rigid structure constraints, the free energy profile can be constructed using line integral along the chosen reference pathway in free energy gradient vector field. We demonstrated that this novel free energy method greatly improve the sampling efficiency through constraints instead of widely applied harmonic restraints. It is proving to be an excellent method to study mechanism of large biological systems, such as enzymes. 5. Combining Conformational Space Annealing (CSA) with Replica Exchange Method (REM) Temperature replica exchange molecular dynamics (T-REM) has been successfully used to improve the conformational search for model peptides and small proteins. However for larger and more complicated systems the use of T-REM is still computationally intensive since the complexity of the free energy landscape and number of replicas required increase with system size. Achieving convergence with systems with slow transition kinetics is also very difficult. Several methods have been proposed to overcome the size and convergence speed issues of standard T-REM. One of these methods is called Reservoir Replica Exchange Method (R-REM) where the conformational search and temperature equilibration are separated. This approach allows integrating computationally efficient search algorithms with replica exchange. The Conformational Space Annealing (CSA) method has been shown to be able to determine the global energy minimum of proteins efficiently and has been used in structure prediction successfully. CSA uses a genetic algorithm approach to generate a diverse set of conformations to determine the minimum energy structure. We have used conformations generated through CSA method to build a reservoir. Replica exchange was then performed where the top replica was seeded with the reservoir structures and fast convergence at every temperature is observed. 6. MDMS: Molecular Dynamics Meta-Simulator for evaluating exchange type sampling methods. Replica exchange methods have become popular tools to explore conformational space for small proteins. For larger biological systems, even with enhanced sampling methods, exploring the free energy landscape remains computationally challenging. This problem has led to the development of many improved replica exchange methods. Unfortunately, testing these methods remains expensive. We developed a Molecular Dynamics Meta-Simulator (MDMS) based on transition state theory to simulate a replica exchange simulation, eliminating the need to run explicit dynamics between exchange attempts. MDMS simulations allow for rapid testing of new replica exchange based methods, greatly reducing the amount of time needed for new method development. Other ongoing projects (listed only, due to annual report character count limits) 7. Participation in the SAMPL3 challenge, Binding free energy methods 8. Using SGLD to enhance Bennett's acceptance ratio (BAR) and Enveloping Distribution Sampling (EDS) convergence 9. pKa calculations with the reservoir pH replica exchange method 10. Using normal mode analysis as a technique to evaluate various coarse grained models 11. Replica exchange and expanded ensemble simulations as Gibbs sampling: Extending Gibbs Sampling to peptides and proteins 12. Efficient Calculation of QM/MM Frequencies with the Mobile Block Hessian (MBH) methods 13. Automatic spot identification for high throughput microarray analysis

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。 1.改进了集合采样的自引导分子动力学（SGLD）模拟方法 自引导分子动力学 Langevin 动力学是为了增强构象搜索而开发的。 该方法使得使用当前可用的计算资源可以观察到常规动力学模拟无法访问的罕见事件。 典型应用包括蛋白质折叠、信号处理、水渗透等。将原始SGLD方法应用于模拟研究时的一个主要挑战是如何定量测量系综偏差以及如何校正SGLD结果。通过分析引导力的特征和SGMD/SGLD模拟行为，我们推导出常规模拟和自引导模拟之间的热力学关系。通过将属性中的低频部分与高频部分分开，我们能够定量描述低频运动的增强并校正构象分布的改变。 这种热力学关系为 SGMD/SGLD 方法的许多应用和扩展铺平了道路。 一个直接的扩展是通过将关系引入到运动方程中，我们开发了 SGMDfp/SGLDfp 方法，该方法可以直接产生正确的构象分布，同时增强构象搜索。 另一个应用是将 SGLD 与副本交换结合起来，无论温度是否升高。 无需温度变化的 SGLD 复制品交换的优点是减少了大型系统（例如溶剂化蛋白质）所需的复制品数量。 2. 多极相互作用的各向同性周期和法 多极相互作用在生物系统中发挥着重要作用，并且越来越多的努力致力于将多极相互作用纳入力场开发中。 多极相互作用的计算费用对于模拟来说是巨大的。 IPS方法为解决这个问题提供了一种便捷的方法。 基于 IPS 概念，我们开发了多极相互作用的 IPS 潜力。 因此，多极相互作用计算可以完全按照截止法进行，以 IPS 势作为切换函数来考虑长程贡献。 3. 一种新颖的刚性结构动力学算法SHAPE 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 模拟中仅应用键长约束，并限制刚体尺寸。我们提出了一种新颖的刚体模拟算法，称为 SHAPE，用于在基于 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。 对包括两种蛋白质在内的四个模型系统的数值测试表明，SHAPE 方法的准确性和可靠性与 SHAKE 方法相当，但具有更高的适用性和效率。 4. 通过刚体模拟沿反应路径自由能法的新算法 利用多个反应坐标（RC）估计反应自由能，尤其是酶促反应，是计算化学和生物学中非常活跃的主题。我们开发了一种高效的新颖算法，在多个 Rc 的约束下沿参考反应路径采样 f 自由能。在此方法中，可以选择定义 RC 的所有关键原子，以在模拟过程中使用我们的 SHAPE 刚体方法作为约束来形成刚性结构。通过一系列具有刚性结构约束的MD模拟，可以使用沿着自由能梯度矢量场中选定的参考路径的线积分来构建自由能剖面。我们证明了这种新颖的自由能方法通过约束而不是广泛应用的谐波约束极大地提高了采样效率。事实证明，它是研究酶等大型生物系统机制的绝佳方法。 5. 构象空间退火 (CSA) 与副本交换方法 (REM) 相结合 温度复制品交换分子动力学 (T-REM) 已成功用于改进模型肽和小蛋白质的构象搜索。然而，对于更大、更复杂的系统，T-REM 的使用仍然是计算密集型的，因为自由能景观的复杂性和所需的副本数量随着系统规模的增加而增加。实现具有慢转变动力学的系统的收敛也非常困难。已经提出了几种方法来克服标准 T-REM 的尺寸和收敛速度问题。其中一种方法称为储库复制品交换法 (R-REM)，其中构象搜索和温度平衡是分开的。这种方法允许将计算效率高的搜索算法与副本交换集成起来。构象空间退火（CSA）方法已被证明能够有效地确定蛋白质的全局能量最小值，并已成功用于结构预测。 CSA 使用遗传算法方法生成一组不同的构象，以确定最小能量结构。我们使用通过CSA方法生成的构象来构建储库。然后进行副本交换，其中顶部副本被植入储层结构，并观察到在每个温度下的快速收敛。 6. MDMS：分子动力学元模拟器，用于评估交换型采样方法。 复制品交换方法已成为探索小蛋白质构象空间的流行工具。对于更大的生物系统，即使采用增强的采样方法，探索自由能景观在计算上仍然具有挑战性。这个问题导致了许多改进的副本交换方法的发展。不幸的是，测试这些方法仍然很昂贵。我们开发了基于过渡态理论的分子动力学元模拟器（MDMS）来模拟副本交换模拟，从而无需在交换尝试之间运行显式动力学。 MDMS 模拟允许快速测试基于副本交换的新方法，从而大大减少新方法开发所需的时间。 其他正在进行的项目（由于年度报告字符数限制，仅列出） 7. 参与SAMPL3挑战，结合自由能方法 8.使用SGLD增强Bennett接受率（BAR）和包络分布采样（EDS）收敛性 9. 使用储层 pH 复制品交换法进行 pKa 计算 10.使用正态模式分析作为评估各种粗粒度模型的技术 11. 副本交换和扩展的集成模拟作为吉布斯采样：将吉布斯采样扩展到肽和蛋白质 12. 使用 Mobile Block Hessian (MBH) 方法有效计算 QM/MM 频率 13. 高通量微阵列分析的自动斑点识别