Role of dynamics in enzyme catalysis: substantial versus semantic controversies.
Role of dynamics in enzyme catalysis: substantial versus semantic controversies.
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DOI：
10.1021/ar500322s
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发表时间：
2015-02-17
影响因子：
18.3
通讯作者：
Kohen A
中科院分区：
文献类型：
--
作者：
Kohen A
酶的动态运动在催化中的作用是当代理论家和实验家激烈争论的中心。解决这些明显的争议是智力和实践的重要性：酶动力学的纳入可能是关键的酶功能的任何计算，并可能有深远的影响，基于结构的药物设计和仿生催化剂的设计。对文献的分析表明，虽然部分争议可能反映了理论方法之间的实质性差异，但大部分辩论是语义上的。例如，一些研究人员在处理与环境处于热平衡的运动时经常使用术语“蛋白质动力学”，而其他研究人员仅将此术语用于非平衡事件。最后一种情况是热能以特定的蛋白质模式“储存”并在其消散到其环境中之前“用于”催化（即，“非统计动力学”）。撇开这个术语问题不谈，理论家们围绕着非统计动力学与统计动力学在催化中的作用展开了一场辩论。然而，据作者所知，目前还没有实验结果可以在酶催化反应中研究这个问题。另一个可能是非实质性争论的来源可能来自酶运动的不同时间尺度，从秒到飞秒不等。不同时间尺度的运动在催化级联反应的许多事件中（反应物结合、反应物的再质子化、结构向过渡态的重排、产物释放等）沿着起着不同的作用。在一些情况下，当各种实验工具被用来探测不同时间尺度上的催化事件时，似乎出现了虚幻的矛盾。在本报告中，沿着讨论了最近对这些问题的利弊进行排序的尝试，以及今后可能的方向。目前研究的一个可能的总结是，酶、底物和溶剂动力学以几种方式对酶催化反应做出贡献：首先通过结合时它们的构象整体的相互“诱导拟合”移动;然后通过构象空间向反应过渡态（TS）的热搜索和势垒向产物跨越的罕见事件，其可能比第一和随后的事件在更快的时间尺度上;最后通过与产物释放相关的动力学，这对于许多酶促反应是限速的。从化学的角度来看，靠近TS，酶系统似乎变硬，限制与化学坐标正交的运动，并使动力学沿着反应坐标选择性地发生。关于酶如何进化以支持不同时间尺度上的有效动力学的研究仍处于起步阶段，需要进一步的实验和计算来揭示酶和非催化反应中的这些现象。
The role of the enzyme’s dynamic motions in catalysis is at the center of heated contemporary debates among both theoreticians and experimentalists. Resolving these apparent disputes is of both intellectual and practical importance: incorporation of enzyme dynamics could be critical for any calculation of enzymatic function and may have profound implications for structure-based drug design and the design of biomimetic catalysts. Analysis of the literature suggests that while part of the dispute may reflect substantial differences between theoretical approaches, much of the debate is semantic. For example, the term “protein dynamics” is often used by some researchers when addressing motions that are in thermal equilibrium with their environment, while other researchers only use this term for nonequilibrium events. The last cases are those in which thermal energy is “stored” in a specific protein mode and “used” for catalysis before it can dissipate to its environment (i.e., “nonstatistical dynamics”). This terminology issue aside, a debate has arisen among theoreticians around the roles of nonstatistical vs statistical dynamics in catalysis. However, the author knows of no experimental findings available today that examined this question in enzyme catalyzed reactions. Another source of perhaps nonsubstantial argument might stem from the varying time scales of enzymatic motions, which range from seconds to femtoseconds. Motions at different time scales play different roles in the many events along the catalytic cascade (reactant binding, reprotonation of reactants, structural rearrangement toward the transition state, product release, etc.). In several cases, when various experimental tools have been used to probe catalytic events at differing time scales, illusory contradictions seem to have emerged. In this Account, recent attempts to sort the merits of those questions are discussed along with possible future directions. A possible summary of current studies could be that enzyme, substrate, and solvent dynamics contribute to enzyme catalyzed reactions in several ways: first via mutual “induced-fit” shifting of their conformational ensemble upon binding; then via thermal search of the conformational space toward the reaction’s transition-state (TS) and the rare event of the barrier crossing toward products, which is likely to be on faster time scales then the first and following events; and finally via the dynamics associated with products release, which are rate-limiting for many enzymatic reactions. From a chemical perspective, close to the TS, enzymatic systems seem to stiffen, restricting motions orthogonal to the chemical coordinate and enabling dynamics along the reaction coordinate to occur selectively. Studies of how enzymes evolved to support those efficient dynamics at various time scales are still in their infancy, and further experiments and calculations are needed to reveal these phenomena in both enzymes and uncatalyzed reactions.
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