Protein dynamics in enzymatic catalysis: Exploration of dihydrofolate reductase
Protein dynamics in enzymatic catalysis: Exploration of dihydrofolate reductase
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DOI：
10.1021/ja9913838
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发表时间：
2000-01-19
影响因子：
15
通讯作者：
Brooks, CL
中科院分区：
文献类型：
--
作者：
Radkiewicz, JL;Brooks, CL
DHFR的整体运动和原子的波动计算使用分子动力学模拟，探索在这个酶系统中的催化和动力学之间的潜在联系。对来自DHFR催化循环的三种三元复合物进行10 ns持续时间的计算：DHFR/DHF/ NADPH（DH）、DHFR/THF/NADP（+）（TP）和DHFR/THF/NADPH（TH）。该蛋白质保持着与初始X射线模型非常相似的核心结构，而几个灵活的环经历构象变化。蛋白质在不同复合物中的动力学比较表明，即使配体仅相差一到两个氢原子，配体也会影响蛋白质的行为。特别是，强耦合的运动，出现在反应配合物DH消失的产品配合物，表明这些运动可能与催化。此外，已观察到的突变体会削弱催化中的特定化学步骤，但在我们的模拟中观察到的蛋白质结构区域中存在高度相关性，以参与高度耦合的运动。我们从我们的分析中得出结论，突变体可以通过改变蛋白质动力学来影响催化作用。
The overall motions and atomic fluctuations of DHFR are calculated using molecular dynamics simulations to explore potential links between catalysis and dynamics in this enzyme system. Calculations of 10 ns duration were performed on three ternary complexes from the DHFR catalytic cycle: DHFR/DHF/ NADPH (DH), DHFR/THF/NADP(+) (TP), and DHFR/THF/NADPH (TH). The protein maintains a core structure very similar to the initial X-ray model, while several flexible loops undergo conformational changes. Comparison of the dynamics of the protein in the different complexes demonstrates that the ligands affect the behavior of the protein even though the ligands only differ by one to two hydrogen atoms. In particular, strong-coupled motions that appear in the reactive complex DH disappear in the product complexes, indicating that these motions may be Linked to catalysis. Furthermore, mutants, which have been observed to be debilitating to particular chemical steps in catalysis, occur with high correlation in the regions of the protein structure observed in our simulations to participate in highly coupled motions. We conclude from our analysis that the mutants could be affecting catalysis by altering the protein dynamics.