Amino-acyl tRNA synthetases are a family of enzymes that play a crucial role in protein synthesis for all living organisms. One such member is prolyl-tRNA synthetase abbreviated hereafter as ProRS, which catalyzes the formation of prolyl-tRNAPro. ProRSs are multi-domain enzymes that display significant variation in domain architecture across species. The “prokaryotic-like” ProRSs contain an insertion (INS) domain between motifs 2 and 3 of the catalytic domain, whereas "eukaryotic-like" ProRSs lack the INS domain. Recent computational and experimental studies revealed that large displacements (global motion) by the INS domain of the “prokaryotic-like” ProRSs along with smaller fluctuations (local motions) in the active site contribute equally to the enzyme’s catalytic efficiency. These global and local motions are known as preorganization and reorganization dynamics, respectively, of the catalytic process. The "eukaryote-like” ProRSs contain a small zinc-binding domain instead of an INS domain. This then begs the question - how do ProRSs of other species use preorganization and reorganization to catalyze the formation of prolyl-tRNAPro even though the enzyme structures are vastly different in nature? To gain an in-depth understanding of the structure-dynamic-function relationship in ProRSs, a comparative study is being conducted using a hybrid QM/MM technique. The two bacterial ProRSs -Enterococcus faecium (INS domain containing) and Rhodopseudomonas palustris (INS domain missing) ProRSs and two “eukaryote-like” ProRSs - Thermus thermophilus and Homo sapiens ProRSs with the zinc-binding domain are chosen for this study. The preliminary results of this study will be presented.

Analysis of intrinsic dynamics to study preorganization in prolyl-tRNA synthetases

ACS Spring 2022

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