UKRI/BBSRC-NSF/BIO: Evolving quantum mechanical tunnelling in enzymes

酶是地球上最有效的催化剂。它们能使化学反应的速度比未催化的反应快1015倍。令人惊讶的是，经过几十年的研究，这种情况发生的方式在许多情况下对化学家和生物学家来说仍然是一个谜。此外，虽然化学受量子力学定律的支配，但在酶促反应中量子力学效应的重要性仍然存在争议。量子原理的使用可能会带来许多技术进步，比如创造不受低温影响的生物催化剂，并具有更广泛的反应性。这个项目探索了利用定向进化技术将这种量子效应嵌入酶功能的方法。一项获得诺贝尔奖的技术，使科学家能够在几个月而不是几千年的时间里利用进化原理在实验室里创造酶的功能。该项目将培养博士生的跨学科研究能力，并通过国际研究合作拓宽他们的经验。酶的功能一直是科学界争论的热点。两个最重要的争议领域是动力学与酶功能耦合的重要性，以及这与量子效应（如隧道效应对酶率的影响）的重要性有什么关系。本项目通过罕见事件采样在酶化学中的应用来探索这一问题。PI是此类研究的先驱，特别是使用过渡路径抽样与提交者分布分析相结合来确定严格的反应坐标。PI还开发了通过路径积分模拟来包含量子动力学的方法。这些将与英国合作者的定向进化实验相结合，他们将在他们的项目中制造优化的人工酶，例如转移氘核而不是质子。这些实验与所描述的项目相结合，将显示量子能力是否可以构建到人工酶中，以及这些能力将允许什么。这项英美合作项目由美国国家科学基金会和英国生物技术和生物科学研究委员会资助，其中美国国家科学基金会资助美国研究者，英国生物科学研究委员会资助英国合作伙伴。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Enzymes are the most effective catalysts on the planet. They have the capability of speeding chemical reactions by a factor of up to 1015 over uncatalyzed reactions. Amazingly, after decades of research, the way this occurs is still in many instances a mystery to chemists and biologists. In addition, while chemistry is governed by the laws of Quantum Mechanics, there is still controversy over the importance of quantum mechanical effects in enzymatic reactions. The use of quantum principles would potentially allow many technological advances such as creating bio-inspired catalysts that were immune to low temperatures and have broader reactivities. This project explores the way such quantum effects may be built into enzyme function using the technology known as directed evolution. A Nobel prize winning technology that allows scientists to create enzyme functions in the laboratory using evolutionary principles in months rather than millennia. This project will train pre-and post-doctoral students in interdisciplinary research and broaden their experience by exposing them to international research collaboration.The functions of enzymes remain a topic of hot debate in the scientific community. Two of the most important areas of controversy are the importance of the coupling of dynamics to enzyme function, and what that has to do with the importance of quantum effects such as tunneling on enzyme rate. This project explores such question through the application of rare event sampling for enzymatic chemistry. The PI has pioneered such studies in particular the use of Transition Path Sampling coupled with committor distribution analysis to identify rigorous reaction coordinates. The PI has also developed methods to include quantum dynamics via path integral simulations. These will be coupled with directed evolution experiments of with UK collaborators who in their projects will craft artificial enzymes optimized for example to transfer deuterons rather than protons. These experiments coupled with the project described will show if quantum capabilities can be built into artificial enzymes, and just what those capabilities will allow. This collaborative US/UK project is supported by the US National Science Foundation and the UK Biotechnology and Biological Sciences Research Council where NSF funds the US investigator and BBSRC funds the UK partner.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.