Ab initio model studies of copper binding to peptides containing a His-His sequence: Relevance to the ß-amyloid peptide of Alzheimer's disease
Por:
Raffa D.F., Gómez-Balderas R., Brunelle P., Rickard G.A., Rauk A.
Publicada:
1 ene 2005
Resumen:
Two of the defining hallmarks of Alzheimer's disease (AD) are deposits of the ?-amyloid peptide, A?, and the generation of reactive oxygen species, both of which may be due to the A? peptide coordinating metal ions. The Cu2+ concentrations in cores of senile plaques are significantly elevated in AD patients. Experimental results indicate that A?1-42 in particular has a very high affinity for Cu2+, and that His13 and His14 are the two most firmly established ligands in the coordination sphere of the copper ion. Quantum chemical calculations using the unrestricted B3LYP hybrid density functional method with the 6-31G(d) basis set were performed for geometries, zero point energies and thermochemistry. The effects of solvation were accommodated using the CPCM method. The enthalpies were calculated with the 6-311+G(2df,2p) basis set. Calculations show that when Cu(H2O) 4 2+ combines with the model compound 1 (3-(1H-imidazol-5-yl)-N-[2-(1H-imidazol-5-yl)ethyl] propanamide) in the aqueous phase, the most stable binding site involves the N? atoms of His13 and His14 as well as the carbonyl of the intervening backbone amide group. These structures are fairly rigid and the implications for conformational changes to the A? backbone are discussed. In solution at pH=7, Cu2+ promotes the deprotonation and involvement in the binding of the backbone amide nitrogen in a ?-sheet like structure. This geometry does not induce strain in the peptide backbone, making it the most likely representation of that portion of the Cu2+-A? complex monomer in aqueous solution. © SBIC 2005.
Filiaciones:
Raffa D.F.:
Department of Chemistry, University of Calgary, 2500 University Drive NW, Calgary, Alta. T2N 1N4, Canada
Gómez-Balderas R.:
Department of Chemistry, University of Calgary, 2500 University Drive NW, Calgary, Alta. T2N 1N4, Canada
Brunelle P.:
Department of Chemistry, University of Calgary, 2500 University Drive NW, Calgary, Alta. T2N 1N4, Canada
Rickard G.A.:
Department of Chemistry, University of Calgary, 2500 University Drive NW, Calgary, Alta. T2N 1N4, Canada
Rauk A.:
Department of Chemistry, University of Calgary, 2500 University Drive NW, Calgary, Alta. T2N 1N4, Canada
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