[论文解读] Protein-Ligand Binding Potential of Mean Force Calculations with Hamiltonian Replica Exchange on Alchemical Interaction Grids

David D. L Minh|arXiv (Cornell University)|Jul 14, 2015

Protein Structure and Dynamics被引用 4

一句话总结

本论文提出一种基于绝热相互作用网格的哈密顿路径从交换方法，用于计算蛋白质-配体结合平均势能（BPMF），采用预计算的静电和范德华网格以及基于热力学长度的状态间距。该方法在约5 kT内实现BPMF标准差的收敛，通过多步自由能循环提升精度，但采样充分性仍对初始配体构象敏感。

ABSTRACT

A binding potential of mean force (BPMF) is a free energy of noncovalent association in which one binding partner is flexible and the other is rigid. I have developed a method to calculate BPMFs for protein-ligand systems. The method is based on replica exchange sampling from multiple thermodynamic states at different temperatures and protein-ligand interaction strengths. Protein-ligand interactions are represented by interpolating precomputed electrostatic and van der Waals grids. Using a simple estimator for thermodynamic length, thermodynamic states are initialized at approximately equal intervals. The method is demonstrated on the Astex diverse set, a database of 85 protein-ligand complexes relevant to pharmacy or agriculture. Fifteen independent simulations of each complex were started using poses from crystallography, docking, or the lowest-energy pose observed in the other simulations. Benchmark simulations completed within three days on a single processor. Overall, protocols initialized using the thermodynamic length estimator were system-specific, robust, and led to approximately even replica exchange acceptance probabilities between neighboring states. In most systems, the standard deviation of the BPMF converges to within 5 kT. Even with low variance, however, the mean BPMF was sometimes dependent on starting conditions, implying inadequate sampling. Within the thermodynamic cycle, free energies estimated based on multiple intermediate states were more precise, and those estimated by single-step perturbation were less precise. The results demonstrate that the method is promising, but that ligand pose sampling and phase space overlap can sometimes prevent precise BPMF estimation. The software used to perform these calculations, Alchemical Grid Dock (AlGDock), is available under the open-source MIT license at this https URL

研究动机与目标

• 开发一种鲁棒且高效的蛋白质-配体结合平均势能（BPMF）计算方法，提升采样效率。
• 解决相空间重叠和配体构象采样带来的挑战，这些挑战阻碍了绝热自由能计算中的精确自由能估算。
• 通过热力学间距排列的绝热状态和预计算的相互作用网格，实现精确的BPMF估算。
• 评估初始配体构象和采样协议对BPMF收敛性和准确性的影响。

提出的方法

• 在不同蛋白质-配体相互作用强度和温度的多个热力学状态下，采用哈密顿路径从交换采样。
• 通过插值预计算的静电和范德华网格图来表示蛋白质-配体相互作用，避免在每一步中重新计算相互作用。
• 采用热力学长度估计器初始化热力学状态，使其大致等间距分布，以确保路径从交换的接受率均衡。
• 应用包含中间状态的多步绝热路径，以提高单步扰动相比的自由能估算精度。
• 使用单个处理器在85个蛋白质-配体复合物的Astex多样性集上运行基准模拟，每个复合物进行15次独立运行。
• 采用一致的自由能循环评估收敛性和准确性，比较单步与多步扰动协议。

实验结果

研究问题

• RQ1 基于热力学长度的绝热状态间距是否能提升蛋白质-配体结合自由能计算中的路径从交换效率和采样性能？
• RQ2 初始配体构象的选择如何影响BPMF估算的收敛性和准确性？
• RQ3 与单步扰动相比，多步绝热自由能循环在多大程度上提升了估算精度？
• RQ4 预计算的相互作用网格是否能在不每次重新计算非键合相互作用的前提下，实现准确且高效的BPMF计算？
• RQ5 相空间重叠和配体构象采样对BPMF估算可靠性有何影响？

主要发现

• 基于热力学长度的状态初始化使相邻状态间的路径从交换接受概率大致均衡，表明采样间距合理有效。
• 在大多数体系中，BPMF的标准差收敛至5 kT以内，表明估算的统计方差较低。
• 尽管方差较低，但BPMF的平均值有时依赖于初始条件，提示由于相空间重叠不足或配体构象采样不佳，采样仍不充分。
• 基于多个中间绝热状态的自由能估算比单步扰动更精确，凸显了多步路径的优势。
• 该方法在系统层面表现出鲁棒性和可行性，所有基准模拟在单个处理器上均于三天内完成。
• 本研究使用的开源软件AlGDock采用MIT许可证发布，支持可重现性并促进广泛应用。