The Influence of Protein Dynamics on the Success of Computational Enzyme Design
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.
Journal of the American Chemical Society
Jory Z. Ruscio, Jonathan E. Kohn, K. Aurelia Ball, Teresa Head Gordon. The influence of protein dynamics on the success of computational enzyme design. Journal of the American Chemical Society, 2009; 131:14111-14115.