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Dynamics on biomolecule energy landscapes: tunnelling in enzymes and kinetics of small peptides
Fri 01 February 2013, 14:00
David Glowacki
University of Bristol
Organiser: Nina Snaith
ABSTRACT
Understanding enzyme catalysis and protein folding are two of the "grand challenges" facing chemical biology. The concept of an energy landscape is coming to dominate thinking in both of these areas. Time permitting, I will discuss how analysis based on multi- state energy landscapes may be utilized to understand experimental observations related to (1) enzyme catalysis and (2) the kinetics of small peptides. Enzyme-catalysed reactions that involve significant quantum tunnelling can give rise to experimental kinetic isotope effects with complex temperature dependences. In some well-studied systems, single state models are unable to describe the experimental observations, raising questions as to the adequacy of standard statistical rate theories like transition state theory (TST). We have recently made progress in understanding a range of controversial experimental observations using a simple multi-state kinetic model.1 A key ingredient of this simple model is the inclusion of (1) appropriate temperature dependences in the tunnelling transmission coefficients, and (2) multiple enzyme-substrate conformations with different reactivity. In contrast to the way that chemists typically think about chemical reaction rates, experimental observations of the kinetics in small peptides often show non-exponential behavior. Particularly dramatic results obtained from photo-initiated initiated studies of the kinetics of small peptides have shown power law kinetics spanning 9 orders of magnitude in time, from picoseconds to milliseconds. Using a recently developed rare-event acceleration method called BXD, we have been able to use atomistic molecular dynamics to investigate the detailed kinetics on arbitrary protein energy landscapes, and recover the same sort of power laws observed by experimentalists.2 These studies provide insight into the mechanisms whereby proteins explore their configuration space with strongly non-equilbrium initial conditions.
(1) Glowacki, D. R.; Harvey, J. N.; Mulholland, A. J. Taking Ockham's razor to enzyme dynamics and catalysis. Nature Chemistry. 2012, 4, 169.
(2) Shalashilin, D. V.; Beddard, G. S.; Paci, E.; Glowacki, D. R. Peptide kinetics from picoseconds to microseconds using Boxed Molecular Dynamics: power law rate coefficients in cyclization reactions. Journal of Chemical Physics. 2012, 137, 9.