论文标题
T4模拟的T4溶菌酶突变体的配体解开机制和动力学
Ligand unbinding mechanisms and kinetics for T4 lysozyme mutants from tauRAMD simulations
论文作者
论文摘要
蛋白质的停留时间Tau影响生物网络中的分子功能，并被认为是药物疗效的重要决定因素。为了预测tau，计算方法必须克服tau通常超过常规分子动力学（MD）仿真的时间尺度的问题。在这里，我们将tau-random加速度分子动力学（TAURAMD）方法应用于一组具有工程结合腔的T4溶菌酶突变体的动力学表征复合物。 taLAMD可以根据实验良好地产生相对的配体解离速率，从而可以全面地表征tau的配体出口路线和决定因素。尽管观察到通过多个出口途径分离配体解离，但我们发现通过主要途径出口决定了tau的值。我们还发现，沿着出口途径的亚稳态的存在减慢了蛋白质 - 配体分离。这些物理见解可以在候选药物的动力学特性的合理优化中得到利用。
The protein-ligand residence time, tau, influences molecular function in biological networks and has been recognized as an important determinant of drug efficacy. To predict tau, computational methods must overcome the problem that tau often exceeds the timescales accessible to conventional molecular dynamics (MD) simulation. Here, we apply the tau-Random Acceleration Molecular Dynamics (tauRAMD) method to a set of kinetically characterized complexes of T4 lysozyme mutants with engineered binding cavities. tauRAMD yields relative ligand dissociation rates in good accordance with experiments and thereby allows a comprehensive characterization of the ligand egress routes and determinants of tau. Although ligand dissociation by multiple egress routes is observed, we find that egress via the predominant route determines the value of tau. We also find that the presence of metastable states along egress pathways slows down protein-ligand dissociation. These physical insights could be exploited in the rational optimization of the kinetic properties of drug candidates.
