Can Free Energy Perturbation Simulations Coupled with Replica-Exchange Molecular Dynamics Study Ligands with Distributed Binding Sites?
Can Free Energy Perturbation Simulations Coupled with Replica-Exchange Molecular Dynamics Study Ligands with Distributed Binding Sites?
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DOI：
10.1021/acs.jcim.3c00631
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发表时间：
2023-08-02
影响因子：
5.6
通讯作者：
Klimov，Dmitri K.
中科院分区：
文献类型：
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作者：
Lockhart，Christopher;Luo，Xingyu;Klimov，Dmitri K.
自由能扰动与溶质调温复制品交换 (FEP/REST) 相结合，提供了一种计算配体相对自由能变化的严格方法。为了确定 FEP/REST 对于具有分布式结合姿势的配体的适用性，我们考虑了两种炼金术转化，涉及委内瑞拉马脑炎病毒核定位信号序列与 importin-α (impα) 转运蛋白结合的三种推定抑制剂 I0、I1 和 I2。 I0 → I1 和 I0 → I2 变换分别增加或减少母体分子的极性。我们的目标有三个：(i) 验证 FEP/REST 技术性能和收敛性，(ii) 估计结合自由能 ΔΔG 的变化，以及 (iii) 确定 FEP/REST 模拟在构象结合分析中的效用。我们的结果如下。首先，我们的 FEP/REST 实现正确遵循 FEP/REST 形式并产生收敛的 ΔΔGestimates。由于配体固有的未结合，更好的FEP/REST策略在于执行多个独立的轨迹而不是延长它们的长度。其次，I0→I1和I0→I2转变导致抑制剂结合自由能总体上发生微小变化，略微增强了I1的亲和力并减弱了I2的亲和力。静电相互作用主导着结合相互作用，决定了焓变。这两种转变引起相反的熵变化，最终控制结合亲和力。重要的是，我们通过将 FEP/REST 自由能估计与我们之前的 REST 模拟进行比较来确认 FEP/REST 自由能估计的有效性，直接探测三个配体与 impα 的结合。第三，我们确定 FEP/REST 模拟可以对配体的结合群进行采样。因此，FEP/REST 可用于 (i) 研究配体结合的能量学，无需定义姿势并显示亲和力 |ΔΔG| 的微小差异。 ≲ 0.5 kcal/mol 和 (ii) 收集配体结合构象集合。
Free energy perturbation coupled with replica exchange with solute tempering (FEP/REST) offers a rigorous approach to compute relative free energy changes for ligands. To determine the applicability of FEP/REST for the ligands with distributed binding poses, we considered two alchemical transformations involving three putative inhibitors I0, I1, and I2 of the Venezuelan equine encephalitis virus nuclear localization signal sequence binding to the importin-α (impα) transporter protein. I0 → I1 and I0 → I2 transformations, respectively, increase or decrease the polarity of the parent molecule. Our objective was three-fold─(i) to verify FEP/REST technical performance and convergence, (ii) to estimate changes in binding free energy ΔΔG, and (iii) to determine the utility of FEP/REST simulations for conformational binding analysis. Our results are as follows. First, our FEP/REST implementation properly follows FEP/REST formalism and produces converged ΔΔGestimates. Due to ligand inherent unbinding, the better FEP/REST strategy lies in performing multiple independent trajectories rather than extending their length. Second, I0 → I1 and I0 → I2 transformations result in overall minor changes in inhibitor binding free energy, slightly strengthening the affinity of I1 and weakening that of I2. Electrostatic interactions dominate binding interactions, determining the enthalpic changes. The two transformations cause opposite entropic changes, which ultimately govern binding affinities. Importantly, we confirm the validity of FEP/REST free energy estimates by comparing them with our previous REST simulations, directly probing binding of three ligands to impα. Third, we established that FEP/REST simulations can sample binding ensembles of ligands. Thus, FEP/REST can be applied (i) to study the energetics of the ligand binding without defined poses and showing minor differences in affinities |ΔΔG| ≲ 0.5 kcal/mol and (ii) to collect ligand binding conformational ensembles.