Post-translational modifications (PTMs) have a profound effect on protein structure and function. One such PTM is the acetylation of a histone (a protein involved in DNA binding). In this reaction, an enzyme catalyzes the transfer of the acetyl group from acetyl CoA to a free lysine on the histone. This transfer neutralizes the positively charged lysine, which ultimately allows the DNA to be exposed for transcription. In our study, we focus on the acetyltransferase, Gcn5. Details regarding the reaction mechanism used by Gcn5 remain obscure. However, current mechanistic hypotheses suggest that the reaction occurs through a tetrahedral oxyanion intermediate, which is stabilized by a hydrogen bond to a nearby residue, i.e. an oxyanion hole. We utilize several computational methods (QM/MM, Metadynamics, Molecular Dynamics) to further probe possible mechanistic schemes of this reaction. We propose a stepwise mechanism proceeding though a tetrahedral, zwitterionic intermediate, which is stabilized by an atypical oxyanion hole geometry.

Computationally investigating the mechanism of the histone acetyltransferase, Gcn5

254th National Meeting (2017)

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