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The influence of protein dynamics on the success of computational enzyme design.

  • Author(s): Ruscio, Jory Z
  • Kohn, Jonathan E
  • Ball, K Aurelia
  • Head-Gordon, Teresa
  • et al.

Published Web Location

https://doi.org/10.1021/ja905396s
Abstract

We characterize the molecular dynamics of a previously described computational de novo designed enzyme optimized to perform a multistep retrol-aldol reaction when engineered into a TIM barrel protein scaffold. The molecular dynamics simulations show that the protein dynamics under physiological conditions of temperature and aqueous environment distorts the designed geometric factors of the substrate-enzyme reaction intermediates, such that catalysis is limited by the primary retrol-aldol step of proton abstraction from the covalently bound substrate and its interactions with a histidine-aspartate dyad. These results emphasize that computational enzyme designs will benefit from considerations of dynamical fluctuations when optimizing active site geometries.

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