Document Detail


The Combined Effects of π-π Stacking and Hydrogen Bonding on the (N1) Acidity of Uracil and Hydrolysis of 2'-Deoxyuridine.
MedLine Citation:
PMID:  22296509     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
M06-2X/6-31+G(d,p) is used to study the simultaneous effects of π-π stacking interactions with phenylalanine (modeled as benzene) and hydrogen bonding with small molecules (HF, H2O and NH3) on the N1 acidity of uracil and the hydrolytic deglycosylation of 2'-deoxyuridine (dU) (facilitated by fully (OH-) or partially (HCOO-•••H2O) activated water). When phenylalanine is complexed with isolated uracil, the proton affinity of all acceptor sites significantly increases (by up to 28 kJ mol-1), while the N1 acidity slightly decreases (by approximately 6 kJ mol-1). When small molecules are hydrogen bound to uracil, addition of the phenylalanine ring can increase or decrease the acidity of uracil depending on the number and nature (acidity) of the molecules bound. Furthermore a strong correlation between the effects of π-π stacking on the acidity of U and the dU deglycosylation reaction energetics is found, where the hydrolysis barrier can increase or decrease depending on the nature and number of small molecules bound, the nucleophile considered (which dictates the negative charge on U in the transition state) and the polarity of the (bulk) environment. These findings emphasize that the catalytic (or anti-catalytic) role of the active-site aromatic amino acid residues is highly dependent on the situation under consideration. In the case of uracil DNA glycosylase (UNG), which catalyzes the hydrolytic excision of uracil from DNA, the type of discrete hydrogen-bonding interactions with U, the nature of the nucleophile and the anticipated weak, nonpolar environment in the active site suggest that phenylalanine will be slightly anti-catalytic in the chemical step and therefore experimentally observed contributions to catalysis may entirely result from associated structural changes that occur prior to deglycosylation.
Authors:
Jennifer Lee Kellie; Lex Navarro-Whyte; Matthew T Carvey; Stacey D Wetmore
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-2-2
Journal Detail:
Title:  The journal of physical chemistry. B     Volume:  -     ISSN:  1520-5207     ISO Abbreviation:  -     Publication Date:  2012 Feb 
Date Detail:
Created Date:  2012-2-2     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101157530     Medline TA:  J Phys Chem B     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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