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

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.

SUBMITTER: Ruscio JZ 

PROVIDER: S-EPMC2918245 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature