Role of protein dynamics in reaction rate enhancement by enzymes
Role of protein dynamics in reaction rate enhancement by enzymes
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DOI：
10.1021/ja055251s
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发表时间：
2005-11-02
影响因子：
15
通讯作者：
Agarwal, PK
中科院分区：
文献类型：
--
作者：
Agarwal, PK
蛋白质结构、动力学和功能的综合观点正在兴起，其中蛋白质被认为是动态活性组装体，内部运动与酶催化等功能密切相关。此外，与蛋白质外部区域结合的溶剂的运动影响内部运动，从而影响蛋白质功能。最近，我们发现了亲环蛋白 A 酶中的蛋白质振动网络，与其肽酰-脯氨酰顺反异构化的催化活性耦合。详细研究表明，这个从表面区域延伸到活性位点的网络是酶结构的保守部分，具有促进催化作用。在本报告中，提出了对所发现的网络内微秒和更长时间尺度上发生的协同构象波动的理论研究。使用新技术，将动能添加到与网络中构象波动相对应的蛋白质振动模式中。结果表明，蛋白质动力学通过改变反应轨迹的过渡态势垒穿越行为来促进催化。观察到随着振动模式动能的增加，传输系数和生产轨迹数量增加。发现过渡态附近活性位点酶-底物相互作用的变化与屏障重穿越相关。模拟还表明，从第一溶剂化壳转移到表面残留物的能量通过网络波动影响催化。这里介绍的网络的详细特征表明蛋白质动力学在酶的速率增强中发挥作用。因此，酶中的耦合网络对于理解变构性和协同效应以及蛋白质工程和药物设计具有广泛的意义。
An integrated view of protein structure, dynamics, and function is emerging, where proteins are considered as dynamically active assemblies and internal motions are closely linked to function such as enzyme catalysis. Further, the motion of solvent bound to external regions of protein impacts internal motions and, therefore, protein function. Recently, we discovered a network of protein vibrations in enzyme cyclophilin A, coupled to its catalytic activity of pepticlyl-prolyl cis-trans isomerization. Detailed studies suggest that this network, extending from surface regions to active site, is a conserved part of enzyme structure and has a role in promoting catalysis. In this report, theoretical investigations of concerted conformational fluctuations occurring on microsecond and longer time scales within the discovered network are presented. Using a new technique, kinetic energy was added to protein vibrational modes corresponding to conformational fluctuations in the network. The results reveal that protein dynamics promotes catalysis by altering transition state barrier crossing behavior of reaction trajectories. An increase in transmission coefficient and number of productive trajectories with increasing amounts of kinetic energy in vibrational modes is observed. Variations in active site enzyme-substrate interactions near transition state are found to be correlated with barrier recrossings. Simulations also showed that energy transferred from first solvation shell to surface residues impacts catalysis through network fluctuations. The detailed characterization of network presented here indicates that protein dynamics plays a role in rate enhancement by enzymes. Therefore, coupled networks in enzymes have wide implications in understanding allostericity and cooperative effects, as well as protein engineering and drug design.