Ubc13 is an E2 enzyme that catalyzes lysine ubiquitination, a type of protein post-translation modification. Ubiquitinating a protein can signal for its degradation and affect its activity. Ubiquitination also plays a role in DNA repair and inflammatory response. Defects in this process are linked to different disorders including cancer, Parkinson’s and Alzheimer’s diseases. The accepted mechanism for Ubc13-catalyzed ubiquitination is a stepwise pathway that proceeds through an oxyanion intermediate. This intermediate is hypothesized to be stabilized by the sidechain of a nearby asparagine residue, which is known as the “oxyanion hole.” However, recent experimental results on mutated Ubc13 have suggested an alternate role for the asparagine. In our study, we use a combination of simulation techniques – classical and <i>ab initio </i>molecular dynamics (MD), quantum mechanics/molecular mechanics (QM/MM), and metadynamics (MTD) – on wild-type and mutated Ubc13 to examine its catalytic mechanism. Our calculations indicate that different intermediates are possible, that water may stabilize the intermediate, and that the asparagine serves to stabilize a random coil near the active site.

Simulations reveal new insights into the mechanism of Ubc13-catalyzed ubiquitination

254th National Meeting (2017)

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