Aviyente, Viktorya

Catak, Saron

De Sterck, Bart

Monard, Gerald

Pauwels, Ewald

Ruiz-Lopez, Manuel F.

Van Speybroeck, Veronique

Waroquier, Michel

Ghent University Academic Bibliography

 13th Intern. Conf. on the Applic. of Density Functional Theory in  Chemistry and Physics, DFT09, Lyon, France.  QM/MM Meta-Dynamics Study of Asparagine Deamidation in Proteins  Saron Cataka,*, Bart De Stercka, Ewald Pauwelsa, Gerald Monardb,  Manuel F. Ruiz-Lópezb, Viktorya Aviyentec, Michel Waroquiera, Veronique Van Speybroecka,*  aCenter for Molecular Modeling, Ghent University, Proeftuinstraat 86, B-9000 Gent, Belgium bEquipe de Chimie et Biochimie Théoriques, UMR CNRS-UHP No. 7565, Nancy-Université, BP 239, 54506 Vandoeuvre-lès-Nancy, France cDepartment of Chemistry, Bogazici University, 34342 Bebek, Istanbul, Turkey * Corresponding authors: saron.catak@ugent.be, veronique.vanspeybroeck@ugent.be    Asparagine (Asn) residues in peptides and proteins are subject to spontaneous non-enzymatic deamidation to form aspartate or iso-aspartate at a rate determined by protein structure and environment [1]. Deamidation causes time-dependent changes in charge and conformation and limits the lifetime of peptides and proteins. This has led to the ‘molecular clocks’ hypothesis [2], which suggests deamidation is a biological molecular timing mechanism that could be set to any desired time interval by genetic control of the primary, secondary, and tertiary structure surrounding the amide. A notable example is Bcl-xL, an anti-apopotic protein that regulates cell death and undergoes a ‘complete loss’ of function upon deamidation; suppression of deamidation in Bcl-xL plays a pivotal role in the survival of tumor cells [1].  Deamidation occurs over a wide range of biologically relevant time intervals; this suggests that different mechanisms may be operative. While a succinimide-mediated deamidation pathway was originally suggested [3-5], two new ‘competing’ routes for deamidation of asparagine residues will be presented. In order to compare relative energetics and feasibilities of plausible routes, QM/MM molecular dynamics simulations, in a periodic water box, were performed on a model peptide. Free energies of competing pathways were calculated via meta-dynamics calculations utilizing the CP2K code [6], where the catalytic effect of water molecules was explicitly analyzed. These calculations have served as a stepping stone for QM/MM metadynamics calculations on deamidation of Bcl-xL.   Keywords: Deamidation, asparagine, Bcl-xL, meta-dynamics, QM/MM, CP2K  [1] Weintraub, S.J. and B.E. Deverman, Sci. STKE., 409, re7 (2007) [2] N. E. Robinson and A. B. Robinson, Proc. Natl. Acad. Sci. USA, 98, 944 (2001)  [3] Kim, E., Lowenson, J. D., MacLaren, D. C., Clarke, S., Proc. Natl. Acad. Sci. USA, 94, 6132 (1997) [4] S. Catak, G. Monard, V. Aviyente and M. F. Ruiz-López, J. Phys. Chem. A, 110, 8354 (2006) [5] S. Catak, G. Monard, V. Aviyente and M. F. Ruiz-López, J. Phys. Chem. A, 113, 1111 (2009) [6] http://cp2k.berlios.de 

QM/MM Meta-Dynamics Study of Asparagine Deamidation in Proteins

https://biblio.ugent.be/publication/765728/file/4134181

QM/MM Meta-Dynamics Study of Asparagine Deamidation in Proteins

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