Origins of the deamidation in peptides and TPI

Deamidation reaction in pentapeptides and the enzyme Trio-sephosphate isomerase (TPI) is investigated by molecular dynamics. For TPI, simulations based on classical AMBER force field are performed in 60 to 90 ns timescale for six distinct samples. Conformational changes, desolvation effects, and hydrogen bond networks are analyzed to interpret the experimental findings. Results that are based on desolvation analysis clarify the experimental results about the different behavior of the two deamidating sites in TPI. Conformational analysis points out that the most favorable reaction mechanism is the one that yields succinimide intermediate via one or two steps as suggested by previous QM studies for peptides.

[1]  Viktorya Aviyente,et al.  Deamidation of asparagine residues: direct hydrolysis versus succinimide-mediated deamidation mechanisms. , 2009, The journal of physical chemistry. A.

[2]  G. Monard,et al.  Computational study on nonenzymatic peptide bond cleavage at asparagine and aspartic acid. , 2008, The journal of physical chemistry. A.

[3]  Viktorya Aviyente,et al.  Reaction mechanism of deamidation of asparaginyl residues in peptides: effect of solvent molecules. , 2006, The journal of physical chemistry. A.

[4]  Jan H. Jensen,et al.  Very fast empirical prediction and rationalization of protein pKa values , 2005, Proteins.

[5]  N. Robinson,et al.  Prediction of primary structure deamidation rates of asparaginyl and glutaminyl peptides through steric and catalytic effects. , 2004, The journal of peptide research : official journal of the American Peptide Society.

[6]  N. Robinson,et al.  Prediction of protein deamidation rates from primary and three-dimensional structure , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[7]  K. Yüksel,et al.  In vitro deamidation of human triosephosphate isomerase. , 1986, Archives of biochemistry and biophysics.

[8]  A. B. Robinson,et al.  Rates of nonenzymatic deamidation of glutaminyl and asparaginyl residues in pentapeptides. , 1973, Journal of the American Chemical Society.

[9]  A. B. Robinson,et al.  Deamidation of glutaminyl and asparaginyl residues in peptides and proteins. , 1974, Current topics in cellular regulation.