Computing Relative Binding Affinity of Ligands to Receptor: An Effective Hybrid Single-Dual-Topology Free-Energy Perturbation Approach in NAMD
Computing Relative Binding Affinity of Ligands to Receptor: An Effective Hybrid Single-Dual-Topology Free-Energy Perturbation Approach in NAMD
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DOI：
10.1021/acs.jcim.9b00362
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发表时间：
2019-09-01
影响因子：
5.6
通讯作者：
Roux, Benoit
中科院分区：
文献类型：
--
作者：
Jiang, Wei;Chipot, Christophe;Roux, Benoit
设计了一种有效的单-双混合拓扑协议，用于计算小配体与受体的相对结合亲和力。该协议是作为NAMD分子动力学程序的扩展而开发的，该程序专门支持相对炼金术自由能摄动（FEP）计算的双拓扑框架。在这个协议中，炼金术的最终状态被表示为两个独立的分子，通过最大结构映射识别出一个共同的子结构。在子结构中，建立原子与原子的对应关系，并在整个模拟过程中对每一对对应的原子进行完整约束，使其始终共享相同的坐标。在传播的每一步，力被投射和组合。根据这个公式，给出了一组可靠的实验/模拟数据的说明性计算，包括小分子的相对溶剂化自由能和药物化合物与蛋白质的相对结合亲和力。为了增强双拓扑区域的采样，在NAMD的多拷贝算法模块支持的复制交换MD方案中进行FEP计算，并定期尝试在相邻状态之间交换热力学耦合参数lambda。结果与文献中报道的实验和基准一致，支持当前方案的有效性。总之，这种混合单-双拓扑方法结合了双拓扑范式的概念简单性和单拓扑方法的优势采样效率，使其成为高通量硅药物设计的理想策略。
An effective hybrid single-dual-topology protocol is designed for the calculation of relative binding affinities of small ligands to a receptor. The protocol was developed as an extension of the NAMD molecular dynamics program, which exclusively supports a dual-topology framework for relative alchemical free-energy perturbation (FEP) calculations. In this protocol, the alchemical end states are represented as two separate molecules sharing a common substructure identified through maximum structural mapping. Within the substructure, an atom-to-atom correspondence is established, and each pair of corresponding atoms is holonomically constrained to share identical coordinates at all time throughout the simulation. The forces are projected and combined at each step for propagation. Following this formulation, a set of illustrative calculations of reliable experiment/simulation data, including relative solvation free energies of small molecules and relative binding affinities of drug compounds to proteins, are presented. To enhance sampling of the dual-topology region, the FEP calculations were carried out within a replica-exchange MD scheme supported by the multiple-copy algorithm module of NAMD, with periodically attempted swapping of the thermodynamic coupling parameter lambda between neighboring states. The results are consistent with experiments and benchmarks reported in the literature, lending support to the validity of the current protocol. In summary, this hybrid single-dual-topology approach combines the conceptual simplicity of the dual-topology paradigm with the advantageous sampling efficiency of the single-topology approach, making it an ideal strategy for high-throughput in silico drug design.