Catalysis in motion: accessing how fast motions facilitate catalysis through pump-probe and fast time resolved spectroscopies.

酶的催化能力的确切来源(S)仍然是一个悬而未决的问题，阻碍了它们在应对当代挑战方面的开发，例如在化学品和材料制造、能源议程和医疗保健方面。虽然静电作用、氢键作用和脱溶作用对过渡态稳定(从而催化)的作用一直被认为发挥着重要作用，但动力学效应--原子在从几秒到飞秒的广泛时间尺度上的运动--的参与和贡献仍然存在争议。特别值得注意的是，最近讨论了动力学效应(振动/运动)与化学(反应)坐标(即键的形成和断裂)的直接耦合，以及这是否提高了酶反应的速度。在这一应用中，重点放在飞秒到皮秒时间尺度上的快速运动以及这种运动与化学反应坐标的可能耦合。其目的是探索它们对本征化学步骤的催化作用和观察到的速度的潜在贡献，为解释它们的影响而开发的模型，以及支持这种运动存在的实验和理论研究。这些运动的潜在重要性在很大程度上源于对酶系统中氢的量子力学隧穿的研究，但与经典的(越障)反应同样相关。挑战是发展对这种运动的原子学理解，并开发更全面的酶催化模型，明确认识到快速动力学在反应障碍跨越中的潜在重要性。这些目标和挑战将在一项创新计划中解决，该计划将飞秒光谱学的新能力与联合光谱学能力、同位素效应分析以及对热或光激活的模型酶催化剂的研究相结合。这是一项真正的跨学科计划，需要超快激光光谱学、物理化学、结构科学、计算和建模/理论方面的专业知识。申请者已经在曼彻斯特大学和哈威尔研究中心组建了一支由这些学科的专家组成的独特团队。他在曼彻斯特建立了在超快光谱和相关领域的领先能力，并为卢瑟福·阿普尔顿实验室飞秒红外光谱新能力的开发和使用做出了贡献。这将使申请者处于行业领先地位，并确保英国具有独特的能力，这将阐明FAST Dynamic在酶系统中的作用。这项工作解决了当代催化研究中一个重要且有争议的假说，该假说直指催化机理的核心。这将导致对生物催化的更全面的了解，从而指导用于合成生物学和工业应用的酶系统的预测性设计，这对新兴的白色(工业)生物技术经济至关重要。

The precise origin(s) of the catalytic power of enzymes remains an unresolved problem that hampers their exploitation in meeting contemporary challenges in, for example, chemicals and materials manufacture, the energy agenda and healthcare. While the role of electrostatic contributions, hydrogen bonding and desolvation to transition state stabilisation (and thus catalysis) have been long recognised as playing an important role, the involvement and contribution of dynamical effects - atomic motions across wide ranging timescales, from seconds to femtoseconds - remains controversial. Of particular note has been recent discussion of the direct coupling of dynamical effects (vibrations/motions) to the chemical (reaction) coordinate (i.e. to the making and breaking of bonds), and whether this enhances the rate of enzymatic reactions. In this application the focus is on fast motions at the femtosecond to picosecond timescale and the possible coupling of such motions to the chemical reaction coordinate. The purpose is to explore their potential contribution to both the catalytic effect on, and the observed rate of, the intrinsic chemical step, the models developed to account for their effect, and the experimental and theoretical studies that support the existence of such motions. The potential importance of these motions has largely arisen from studies of quantum mechanical tunnelling of hydrogen in enzyme systems, but is equally relevant to classical (over-the-barrier) reactions. The challenge is to develop atomistic understanding of such motions and develop more comprehensive models of enzyme catalysis that explicitly recognise the potential importance of fast dynamics in reaction barrier crossing. These aims and challenges will be addressed in an innovative programme integrating new capabilities in femtosecond spectroscopy with allied spectroscopy capabilities, isotope effect analysis and studies of model enzyme catalysts that are activated either thermally or by light.This is a truly cross disciplinary programme requiring expertise in ultrafast laser spectroscopy, physical chemistry, structural science, computation and modelling/theory. The applicant has assembled a unique team of experts across these disciplines based at the University of Manchester and the Harwell Research Complex. He has established leading capabilities in ultrafast spectrocopy and allied areas at Manchester and contributed to the development and use of new capabilities at Rutherford Appleton Laboratory in femtosecond IR spectroscopy. This combines to place the applicant in field-leading position and secure for the UK unique capabilities that will elucidate the role of fast dynamics in enzyme systems. The work addresses a major and controversial hypothesis in contemporary catalysis research which goes to the very heart of catalysis mechanisms. This will lead to more comprehensive understanding of bio-catalysis that will guide the predictive design of enzyme systems for use in synthetic biology and industrial applications, which is crucial to the emerging white (industrial) biotechnology economy.