Title

Computation Insights into the Amino Acid Activation by Class I TrpRS and GluRS and Class II AspRS

Streaming Media

Type of Proposal

Digital Poster

Start Date

31-3-2017 1:00 PM

End Date

31-3-2017 2:00 PM

Faculty

Faculty of Science

Faculty Sponsor

Dr. James Gauld

Abstract

Abstract Aminoacyl-tRNA synthetases (aaRSs) are an ancient family of enzymes implicated in viral assembly, proliferation of cancer cells, and mitochondrial dysfunction leading to inflammation and ultimately apoptosis. They catalyze the addition of an amino acid to its cognate tRNA in protein biosynthesis via two half-reactions referred to as: (i)activation where the amino acid is reacted with ATP to produce an activated intermediate, and (ii) aminoacylation where the amino acyl moiety from the previous reaction is transferred to the cognate tRNA. AaRSs are divided into two classes, I or II, depending on whether the amino acid's syn- (Class I) or anti-oxygen (Class II) nucleophilically attacks the α-phosphate of ATP to activate the amino acid. Unlike all other Class I aaRSs, however, in TrpRS the anti-oxygen acts as this mechanistically critical nucleophile! Computational chemistry uses computers to model the properties and reactions of chemical systems. Notably, it enables us to, for instance, examine the interactions and reactions molecules at the atomic level. The aim of our present research is to understand why Class I TrpRS behaves like a Class II aaRS. More specifically, the goal is to use the computational molecular dynamics simulations to determine: (i) the structure of TrpRS within the cellular environment, (ii) how TrpRS binds its amino acid (Trp) and ATP substrates, and (iii) the impact of active site mutations on substrate binding. The initial results of these studies have helped to identify features and chemical functional groups within the active site of TrpRS that influence substrate positioning, a key factor in determining the mode and direction of attack of the anti-oxygen of Trp on ATP. This information is essential for understanding the catalytic mechanism of this essential enzyme, and furthermore a key step towards designing targeted drugs.

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Mar 31st, 1:00 PM Mar 31st, 2:00 PM

Computation Insights into the Amino Acid Activation by Class I TrpRS and GluRS and Class II AspRS

Abstract Aminoacyl-tRNA synthetases (aaRSs) are an ancient family of enzymes implicated in viral assembly, proliferation of cancer cells, and mitochondrial dysfunction leading to inflammation and ultimately apoptosis. They catalyze the addition of an amino acid to its cognate tRNA in protein biosynthesis via two half-reactions referred to as: (i)activation where the amino acid is reacted with ATP to produce an activated intermediate, and (ii) aminoacylation where the amino acyl moiety from the previous reaction is transferred to the cognate tRNA. AaRSs are divided into two classes, I or II, depending on whether the amino acid's syn- (Class I) or anti-oxygen (Class II) nucleophilically attacks the α-phosphate of ATP to activate the amino acid. Unlike all other Class I aaRSs, however, in TrpRS the anti-oxygen acts as this mechanistically critical nucleophile! Computational chemistry uses computers to model the properties and reactions of chemical systems. Notably, it enables us to, for instance, examine the interactions and reactions molecules at the atomic level. The aim of our present research is to understand why Class I TrpRS behaves like a Class II aaRS. More specifically, the goal is to use the computational molecular dynamics simulations to determine: (i) the structure of TrpRS within the cellular environment, (ii) how TrpRS binds its amino acid (Trp) and ATP substrates, and (iii) the impact of active site mutations on substrate binding. The initial results of these studies have helped to identify features and chemical functional groups within the active site of TrpRS that influence substrate positioning, a key factor in determining the mode and direction of attack of the anti-oxygen of Trp on ATP. This information is essential for understanding the catalytic mechanism of this essential enzyme, and furthermore a key step towards designing targeted drugs.