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

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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.