In recent years, there has been a significant debate about the extent to which protein conformational dynamics plays a role in enzyme catalysis. Even fuzzier is, however, the extent to which the fine-tuning of the catalytic conformations of enzymes can act as a driving force for molecular evolution. In particular, the triosephosphate isomerase (βα)<sub>8</sub> fold (TIM-barrel fold) enzymes have been instructive and easily evolvable model systems to probe the conformational dynamics hypothesis. Our choice of methods is a wide range of enhanced-sampling molecular dynamics techniques (<i>e.g.</i>, umbrella sampling, metadynamics, replica exchange) to study enzyme dynamics, and empirical valence bond method to probe the reaction mechanisms. In the present contribution, we showcase how conformational sampling works at multiple timescales and levels of protein structure (from side-chain dynamics to big loop motion, to TIM-barrel core breathing), and provide direct implications of conformational sampling on the underlying reaction mechanisms in various TIM-barrel enzymes.

Effects of conformational dynamics on enzyme evolution in TIM-barrel-fold proteins

256th National Meeting (2018)

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