Multiscale enhanced sampling of glucokinase: Regulation of the enzymatic reaction via a large scale domain motion
Multiscale enhanced sampling of glucokinase: Regulation of the enzymatic reaction via a large scale domain motion
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DOI：
10.1063/1.5027444
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发表时间：
2018-08-21
影响因子：
4.4
通讯作者：
Kidera, Akinori
中科院分区：
文献类型：
--
作者：
Moritsugu, Kei;Terada, Tohru;Kidera, Akinori
增强的采样产生了全面的结构系综或自由能图景，这超出了传统的分子动力学模拟的能力。我们最近开发的多尺度增强采样(MSES)方法使用粗粒度模型与目标物理系统相结合来有效地加速动力学。MSES已被证明适用于溶液中的大蛋白质系统，如固有的无序蛋白质和蛋白质-蛋白质和蛋白质-配体相互作用。在这里，我们将MSES模拟应用于一个重要的药物发现目标--葡萄糖激酶(GCK)，以阐明在原子分辨率下酶反应的正协同性的结构基础。MSES使我们能够比较葡萄糖结合形式和非结合形式两组GCK的自由能谱，从而证明了自由能面随葡萄糖浓度的变化而剧烈变化。在葡萄糖结合的形式中，我们发现了两个不同的盆地，由高能屏障分隔，源于结构域运动和阿尔法13螺旋的折叠/展开。相比之下，在葡萄糖无结合状态下，单个平坦的盆地延伸到开放和超开放状态。这些特征说明了实现协同作用的两个截然不同的阶段，即在高糖浓度下快速反应周期处于闭合状态，而在低浓度时主要处于开放/超开放状态的慢循环。加权系综模拟揭示了GCK的结构变化与MSES结果协同作用的动力学过程：闭态与开态/超开态之间的转变速率常数k(C/O)=1.1ms(-1)与实验催化速率k(CAT)=0.22ms(-1)的数量级相同。最后，我们讨论了GCK激活剂(调节GCK活性的小分子药物)的药理活性，从结构域运动的微小变化出发，依赖于它们的化学结构作为调节剂。本研究证明了增强采样和相关的动力学计算的能力，以了解生理环境中蛋白质系统的原子结构动力学。由AIP出版公司出版。
Enhanced sampling yields a comprehensive structural ensemble or a free energy landscape, which is beyond the capability of a conventional molecular dynamics simulation. Our recently developed multiscale enhanced sampling (MSES) method employs a coarse-grained model coupled with the target physical system for the efficient acceleration of the dynamics. MSES has demonstrated applicability to large protein systems in solution, such as intrinsically disordered proteins and protein-protein and protein-ligand interactions. Here, we applied the MSES simulation to an important drug discovery target, glucokinase (GCK), to elucidate the structural basis of the positive cooperativity of the enzymatic reaction at an atomistic resolution. MSES enabled us to compare two sets of the free energy landscapes of GCK, for the glucose-bound and glucose-unbound forms, and thus demonstrated the drastic change of the free energy surface depending on the glucose concentration. In the glucose-bound form, we found two distinct basins separated by a high energy barrier originating from the domain motion and the folding/unfolding of the alpha 13 helix. By contrast, in the glucose-unbound form, a single flat basin extended to the open and super-open states. These features illustrated the two distinct phases achieving the cooperativity, the fast reaction cycle staying in the closed state at a high glucose concentration and the slow cycle primarily in the open/super-open state at a low concentration. The weighted ensemble simulations revealed the kinetics of the structural changes in GCK with the synergetic use of the MSES results; the rate constant of the transition between the closed state and the open/super-open states, k(C/O) = 1.1 ms (-1), is on the same order as the experimental catalytic rate, k(cat) = 0.22 ms (-1). Finally, we discuss the pharmacological activities of GCK activators (small molecular drugs modulating the GCK activity) in terms of the slight changes in the domain motion, depending on their chemical structures as regulators. The present study demonstrated the capability of the enhanced sampling and the associated kinetic calculations for understanding the atomistic structural dynamics of protein systems in physiological environments. Published by AIP Publishing.