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Computational study on nonenzymatic peptide bond cleavage at asparagine and aspartic acid

Saron Catak UGent, Gerald Monard, Viktorya Aviyente and Manuel F Ruiz-Lopez (2008) JOURNAL OF PHYSICAL CHEMISTRY A. 112(37). p.8752-8761
abstract
Nonenzymatic peptide bond cleavage at asparagine (Asn) and glutamine (Gln) residues has been observed during peptide deamidation experiments; cleavage has also been reported at aspartic acid (Asp) and glutamic acid (Gin) residues. Although peptide backbone cleavage at Asn is known to be slower than deamidation, fragmentation products are often observed during peptide deamidation experiments. In this study, mechanisms leading to the cleavage of the carboxyl-side peptide bond of Asn and Asp residues were investigated using computational methods (B3LYP/6-31+G**). Single-point solvent calculations at the B3LYP/6-31++G** level were carried out in water, utilizing the integral equation formalism-polarizable continuum (IEF-PCM) model. Mechanism and energetics of peptide fragmentation at Asn were comparatively analyzed with previous calculations on deamidation of Asn. When deamidation proceeds through direct hydrolysis of the Asn side chain or through cyclic imide formation-via a tautomerization route-it exhibits lower activation barriers than peptide bond cleavage at Asn. The fundamental distinction between the mechanisms leading to deamidation-via a succinimide-and backbone cleavage was found to be the difference in nucleophilic entities involved in the cyclization process (backbone versus side-chain amide nitrogen). If deamidation is prevented by protein three-dimensional structure, cleavage may become a competing pathway. Fragmentation of the peptide backbone at Asp was also computationally studied to understand the likelihood of Asn deamidation preceding backbone cleavage. The activation barrier for backbone cleavage at Asp residues is much lower (approximately 10 kcal/mol) than that at Asn. This suggests that peptide bond cleavage at Asn residues is more likely to take place after it has deamidated into Asp.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
ANISOTROPIC DIELECTRICS, SUCCINIMIDE, MECHANISM, HYDROLYSIS, DEGRADATION, 3-DIMENSIONAL STRUCTURE, DEAMIDATION RATES, RESIDUES, GLUTAMINYL, AB-INITIO
journal title
JOURNAL OF PHYSICAL CHEMISTRY A
J. Phys. Chem. A
volume
112
issue
37
pages
8752 - 8761
publisher
AMER CHEMICAL SOC
place of publication
Washington, USA
Web of Science type
Article
Web of Science id
000259140400035
JCR category
PHYSICS, ATOMIC, MOLECULAR & CHEMICAL
JCR impact factor
2.871 (2008)
JCR rank
7/31 (2008)
JCR quartile
1 (2008)
ISSN
1089-5639
DOI
10.1021/jp8015497
language
English
UGent publication?
no
classification
A1
id
498164
handle
http://hdl.handle.net/1854/LU-498164
date created
2009-02-19 12:23:50
date last changed
2017-01-02 09:55:58
@article{498164,
  abstract     = {Nonenzymatic peptide bond cleavage at asparagine (Asn) and glutamine (Gln) residues has been observed during peptide deamidation experiments; cleavage has also been reported at aspartic acid (Asp) and glutamic acid (Gin) residues. Although peptide backbone cleavage at Asn is known to be slower than deamidation, fragmentation products are often observed during peptide deamidation experiments. In this study, mechanisms leading to the cleavage of the carboxyl-side peptide bond of Asn and Asp residues were investigated using computational methods (B3LYP/6-31+G**). Single-point solvent calculations at the B3LYP/6-31++G** level were carried out in water, utilizing the integral equation formalism-polarizable continuum (IEF-PCM) model. Mechanism and energetics of peptide fragmentation at Asn were comparatively analyzed with previous calculations on deamidation of Asn. When deamidation proceeds through direct hydrolysis of the Asn side chain or through cyclic imide formation-via a tautomerization route-it exhibits lower activation barriers than peptide bond cleavage at Asn. The fundamental distinction between the mechanisms leading to deamidation-via a succinimide-and backbone cleavage was found to be the difference in nucleophilic entities involved in the cyclization process (backbone versus side-chain amide nitrogen). If deamidation is prevented by protein three-dimensional structure, cleavage may become a competing pathway. Fragmentation of the peptide backbone at Asp was also computationally studied to understand the likelihood of Asn deamidation preceding backbone cleavage. The activation barrier for backbone cleavage at Asp residues is much lower (approximately 10 kcal/mol) than that at Asn. This suggests that peptide bond cleavage at Asn residues is more likely to take place after it has deamidated into Asp.},
  author       = {Catak, Saron and Monard, Gerald and Aviyente, Viktorya and Ruiz-Lopez, Manuel F},
  issn         = {1089-5639},
  journal      = {JOURNAL OF PHYSICAL CHEMISTRY A},
  keyword      = {ANISOTROPIC DIELECTRICS,SUCCINIMIDE,MECHANISM,HYDROLYSIS,DEGRADATION,3-DIMENSIONAL STRUCTURE,DEAMIDATION RATES,RESIDUES,GLUTAMINYL,AB-INITIO},
  language     = {eng},
  number       = {37},
  pages        = {8752--8761},
  publisher    = {AMER CHEMICAL SOC},
  title        = {Computational study on nonenzymatic peptide bond cleavage at asparagine and aspartic acid},
  url          = {http://dx.doi.org/10.1021/jp8015497},
  volume       = {112},
  year         = {2008},
}

Chicago
Catak, Saron, Gerald Monard, Viktorya Aviyente, and Manuel F Ruiz-Lopez. 2008. “Computational Study on Nonenzymatic Peptide Bond Cleavage at Asparagine and Aspartic Acid.” Journal of Physical Chemistry A 112 (37): 8752–8761.
APA
Catak, S., Monard, G., Aviyente, V., & Ruiz-Lopez, M. F. (2008). Computational study on nonenzymatic peptide bond cleavage at asparagine and aspartic acid. JOURNAL OF PHYSICAL CHEMISTRY A, 112(37), 8752–8761.
Vancouver
1.
Catak S, Monard G, Aviyente V, Ruiz-Lopez MF. Computational study on nonenzymatic peptide bond cleavage at asparagine and aspartic acid. JOURNAL OF PHYSICAL CHEMISTRY A. Washington, USA: AMER CHEMICAL SOC; 2008;112(37):8752–61.
MLA
Catak, Saron, Gerald Monard, Viktorya Aviyente, et al. “Computational Study on Nonenzymatic Peptide Bond Cleavage at Asparagine and Aspartic Acid.” JOURNAL OF PHYSICAL CHEMISTRY A 112.37 (2008): 8752–8761. Print.