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Promotionsvortrag Physik: "Computational modeling of glycyl radical enzymes: Novel insights to the mechanism of Pyruvate Formate-Lyase"

Okt 30
30. Oktober 2020 10:00 Uhr bis 11:00 Uhr
Die Prüfung findet online unter Ausschluss der Öffentlichkeit statt

Ankündigung des Promotionsvortrags von: Marko Hanzevacki

Glycyl radical enzymes (GREs) catalyze key biochemical reactions in the microbial metabolism and the environment by employing a highly reactive glycyl radical intermediate. In this work, the multiscale computational modeling has been applied to reveal the elusive steps in the catalytic mechanism of pyruvate formate-lyase (PFL), a member of the GREs family that operates in the central anaerobic glucose catabolism of E. coli where it converts pyruvate and coenzyme A (CoA) into formate and acetyl-CoA in two half-reactions.

In the first part of the lecture, we performed the extensive molecular dynamics (MD) simulations of monomeric and dimeric PFL enzymatic systems before and after the first half-reaction to explore the influence of chemical change in the active site on protein dynamics. We demonstrated that the acetylation of Cys418 induces the opening of the CoA entry channel on the protein surface.

In the second part, we exploited enhanced sampling MD simulations and free energy methods to explore stable and reactive bound states in which CoA resides near the active site. While the increased energy cost for CoA binding into the active site was observed in all examined cases, we showed that the spontaneous dissociation of CoA from the active site is less likely after the first half-reaction indicating a stronger complex between CoA and the active site residues.

Using previously characterized bound conformations of CoA in the active site, we performed quantum mechanics/molecular mechanics (QM/MM) calculations of both half-reactions. The calculated energy profiles suggest that the activation of CoA is carried out by CO2•− rather than Cys419• as proposed earlier. This systematic work contains results that significantly contribute to a better understanding of the catalytic mechanism in PFL, especially the elusive role of CoA in the second half-reaction.
(Vortrag auf Englisch)

Dem Vortrag schließt sich eine Diskussion von 15 Minuten an. Vortrag und Diskussion sind aufgrund der momentanen Situation nicht öffentlich. Diesen Verfahrensteilen folgt ein ebenfalls nicht öffentliches Rigorosum von 45 Minuten.