Molecular recognition of aldehydes by aldehyde dehydrogenase and mechanism of nucleophile activation

Proteins
Troy WymoreDavid W Deerfield

Abstract

Experimental structural data on the state of substrates bound to class 3 Aldehyde Dehydrogenases (ALDH3A1) is currently unknown. We have utilized molecular mechanics (MM) simulations, in conjunction with new force field parameters for aldehydes, to study the atomic details of benzaldehyde binding to ALDH3A1. Our results indicate that while the nucleophilic Cys243 must be in the neutral state to form what are commonly called near-attack conformers (NACs), these structures do not correlate with increased complexation energy calculated with the MM-Generalized Born Molecular Volume (GBMV) method. The negatively charged Cys243 (thiolate form) of ALDH3A1 also binds benzaldehyde in a stable conformation but in this complex the sulfur of Cys243 is oriented away from benzaldehyde yet yields the most favorable MM-GBMV complexation energy. The identity of the general base, Glu209 or Glu333, in ALDHs remains uncertain. The MM simulations reveal structural and possible functional roles for both Glu209 and Glu333. Structures from the MM simulations that would support either glutamate residue as the general base were further examined with Hybrid Quantum Mechanical (QM)/MM simulations. These simulations show that, with the PM3/OPLS potential, ...Continue Reading

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Citations

Feb 6, 2013·Journal of Agricultural and Food Chemistry·Pierluigi CaboniGraziella Tocco
May 5, 2011·The Journal of Biological Chemistry·Yaroslav Tsybovsky, Sergey A Krupenko
Feb 15, 2013·The Journal of Biological Chemistry·David KopečnySolange Moréra
Mar 19, 2016·ACS Chemical Biology·Stiti NaimRenier A L van der Hoorn
Jan 27, 2015·Chemico-biological Interactions·Rosario A Muñoz-ClaresAdriana Julián-Sánchez
Feb 26, 2015·Proceedings of the National Academy of Sciences of the United States of America·Che-Hong ChenDaria Mochly-Rosen
Jan 20, 2009·The Journal of Physical Chemistry. B·Kaicong Cai, Jianping Wang
Jul 28, 2019·ACS Catalysis·Attabey Rodríguez BenítezAlison R H Narayan

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