近日，英国布里斯托大学教授Adrian J. Mulholland及其团队的研究发现动态网络演化增强了设计酶的催化作用。这一研究成果于2021年8月19日发表在国际顶尖学术期刊《自然—化学》上。

研究小组展示了一个计算设计的坎普消除酶的定向进化重塑蛋白质动力学，这导致了在原始设计中没有的活化热容量的提高。这些变化有助于过渡状态的稳定。广泛的分子动力学模拟表明，演化的结果是封闭的溶剂暴露环和一个更好的包装的活性位点。

值得注意的是，这产生了一个相关的动态网络，涉及过渡状态和蛋白质的大部分。该网络收紧了过渡态系综，导致了活化热容的负性和活度-温度依赖性的非线性。他们的研究结果对理解酶的进化具有启示意义，并表明通过设计和进化选择性地瞄准过渡态集合的构象动力学将加速新型酶的产生。

据介绍，从许多天然酶的非阿仑尼乌斯行为可以看出，活化热容正逐渐成为酶热适应的关键因素。然而，它的物理起源及其与催化活性演化的关系尚不明确。

附：英文原文

Title: Evolution of dynamical networks enhances catalysis in a designer enzyme

Author: Bunzel, H. Adrian, Anderson, J. L. Ross, Hilvert, Donald, Arcus, Vickery L., van der Kamp, Marc W., Mulholland, Adrian J.

Issue&Volume: 2021-08-19

Abstract: Activation heat capacity is emerging as a crucial factor in enzyme thermoadaptation, as shown by the non-Arrhenius behaviour of many natural enzymes. However, its physical origin and relationship to the evolution of catalytic activity remain uncertain. Here we show that directed evolution of a computationally designed Kemp eliminase reshapes protein dynamics, which gives rise to an activation heat capacity absent in the original design. These changes buttress transition-state stabilization. Extensive molecular dynamics simulations show that evolution results in the closure of solvent-exposed loops and a better packing of the active site. Remarkably, this gives rise to a correlated dynamical network that involves the transition state and large parts of the protein. This network tightens the transition-state ensemble, which induces a negative activation heat capacity and non-linearity in the activity–temperature dependence. Our results have implications for understanding enzyme evolution and suggest that selectively targeting the conformational dynamics of the transition-state ensemble by design and evolution will expedite the creation of novel enzymes.

DOI: 10.1038/s41557-021-00763-6

Source: https://www.nature.com/articles/s41557-021-00763-6