Department of Chemistry, California Institute for Quantitative Sciences, University of California, Berkeley, California 94720, USA.
Annu Rev Biochem. 2013;82:471-96. doi: 10.1146/annurev-biochem-051710-133623.
The relationship between protein dynamics and function is a subject of considerable contemporary interest. Although protein motions are frequently observed during ligand binding and release steps, the contribution of protein motions to the catalysis of bond making/breaking processes is more difficult to probe and verify. Here, we show how the quantum mechanical hydrogen tunneling associated with enzymatic C-H bond cleavage provides a unique window into the necessity of protein dynamics for achieving optimal catalysis. Experimental findings support a hierarchy of thermodynamically equilibrated motions that control the H-donor and -acceptor distance and active-site electrostatics, creating an ensemble of conformations suitable for H-tunneling. A possible extension of this view to methyl transfer and other catalyzed reactions is also presented. The impact of understanding these dynamics on the conceptual framework for enzyme activity, inhibitor/drug design, and biomimetic catalyst design is likely to be substantial.
蛋白质动力学与功能之间的关系是当前备受关注的课题。尽管在配体结合和释放步骤中经常观察到蛋白质运动，但蛋白质运动对形成/断裂键过程的催化作用更难探测和验证。在这里，我们展示了与酶促 C-H 键断裂相关的量子力学氢隧穿如何为理解蛋白质动力学对于实现最佳催化的必要性提供了独特的视角。实验结果支持了一系列热力学平衡运动的层次结构，这些运动控制着 H 供体和受体的距离以及活性位点的静电作用，从而形成了适合氢隧穿的构象组合。还提出了这种观点对甲基转移和其他催化反应的可能扩展。理解这些动力学对酶活性、抑制剂/药物设计和仿生催化剂设计的概念框架的影响可能是巨大的。
