Document Detail

pKa determination of histidine residues in α-conotoxin MII peptides by 1H NMR and constant pH molecular dynamics simulation.
MedLine Citation:
PMID:  23336579     Owner:  NLM     Status:  MEDLINE    
α-Conotoxin MII (α-CTxMII) is a potent and selective peptide antagonist of neuronal nicotinic acetylcholine receptors (nAChR's). Studies have shown that His9 and His12 are significant determinants of toxin binding affinity for nAChR, while Glu11 may dictate differential toxin affinity between nAChR isoforms. The protonation state of these histidine residues and therefore the charge on the α-CTx may contribute to the observed differences in binding affinity and selectivity. In this study, we assess the pH dependence of the protonation state of His9 and His12 by (1)H NMR spectroscopy and constant pH molecular dynamics (CpHMD) in α-CTxMII, α-CTxMII[E11A], and the triple mutant, α-CTxMII[N5R:E11A:H12K]. The E11A mutation does not significantly perturb the pKa of His9 or His12, while N5R:E11A:H12K results in a significant decrease in the pKa value of His9. The pKa values predicted by CpHMD simulations are in good agreement with (1)H NMR spectroscopy, with a mean absolute deviation from experiment of 0.3 pKa units. These results support the use of CpHMD as an efficient and inexpensive predictive tool to determine pKa values and structural features of small peptides critical to their function.
Owen M McDougal; David M Granum; Mark Swartz; Conrad Rohleder; C Mark Maupin
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2013-02-25
Journal Detail:
Title:  The journal of physical chemistry. B     Volume:  117     ISSN:  1520-5207     ISO Abbreviation:  J Phys Chem B     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-03-07     Completed Date:  2013-08-12     Revised Date:  2014-03-10    
Medline Journal Info:
Nlm Unique ID:  101157530     Medline TA:  J Phys Chem B     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2653-61     Citation Subset:  IM    
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MeSH Terms
Conotoxins / chemistry*
Histidine / chemistry*
Hydrogen-Ion Concentration
Magnetic Resonance Spectroscopy
Molecular Dynamics Simulation*
Peptides / chemistry*
Grant Support
Reg. No./Substance:
0/Conotoxins; 0/Peptides; 0/alpha-conotoxin MII; 4QD397987E/Histidine

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