The intrinsic dynamics that are inherent in proteins are known to be critical for many important biochemical processes. However, there is still limited information regarding how dynamics favor enzymes to achieve their enormous rate enhancement. To better understand the molecular mechanism of the interplay between dynamics and catalysis, we are currently modeling an important biochemical reaction known as prolyl-adenylate formation. This reaction is catalyzed by prolyl-tRNA synthetase, a member of the aminoacyl-tRNA synthetases family. We are using quantum mechanical/molecular mechanical approaches to model and compute energetics of the adenylate formation reaction in enzyme and enzyme-free (aqueous) system. In this simulated model, the proline and the triphosphate group of the ATP has been treated with self-consistent charge density functional tight-binding (SCC-DFTB) method, while the protein and solvent atoms are treated by classical mechanics. Similar simulations are being performed with mutant enzymes generated by site-directed mutagenesis of residues at the hinge regions and independent dynamic segments. Herein, we will present the preliminary results, which will include the energetics of prolyl-adenylate formation for the wild type and mutant enzymes, analysis of their intrinsic dynamics and comparative experimental kinetic analysis of the wild-type and mutant enzymes.

Exploring the interplay of dynamics and catalysis in <i>Escherichia coli</i> prolyl-tRNA synthetase using quantum mechanical/molecular mechanical simulations

251st National Meeting (2016)

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Exploring the interplay of dynamics and catalysis in Escherichia coli prolyl-tRNA synthetase using quantum mechanical/molecular mechanical simulations