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Insights into the oxygen-based ligand of the low pH component of the Cu(2+)-amyloid-β complex.
J Phys Chem B. 2014 Aug 28; 118(34):10052-64.JP

Abstract

In spite of significant experimental effort dedicated to the study of Cu(2+) binding to the amyloid beta (Aβ) peptide, involved in Alzheimer's disease, the nature of the oxygen-based ligand in the low pH component of the Cu(2+)-Aβ(1-16) complex is still under debate. This study reports density-functional-theory-based calculations that explore the potential energy surface of Cu(2+) complexes including N and O ligands at the N-terminus of the Aβ peptide, with a focus on evaluating the role of Asp1 carboxylate in copper coordination. Model conformers including 3, 6, and 17 amino acids have been used to systematically study several aspects of the Cu(2+)-coordination such as the Asp1 side chain conformation, local peptide backbone geometry, electrostatic and/or hydrogen bond interactions, and number and availability of Cu(2+) ligands. Our results show that the Asp1 peptide carbonyl binds to Cu(2+) only if the coordination number is less than four. In contrast, if four ligands are available, the most stable structures include the Asp1 carboxylate in equatorial position instead of the Asp1 carbonyl group. The two lowest energy Cu(2+)-Aβ(1-17) models involve Asp1 COO(-), the N-terminus, and His6 and His14 as equatorial ligands, with either a carbonyl or a water molecule in the axial position. These models are in good agreement with experimental data reported for component I of the Cu(2+)-Aβ(1-16) complex, including EXAFS- and X-ray-derived Cu(2+)-ligand distances, Cu(2+) EPR parameters, and (14)N and (13)C superhyperfine couplings. Our results suggest that at low pH, Cu(2+)-Aβ species with Asp1 carboxylate equatorial coordination coexist with species coordinating the Asp1 carbonyl. Understanding the bonding mechanism in these species is relevant to gain a deeper insight on the molecular processes involving copper-amyloid-β complexes, such as aggregation and redox activity.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Gomez-Castro CZ
Departamento de Química, Cinvestav , Avenida Instituto Politécnico Nacional 2508, México D.F. 07360, México.
Vela A
No affiliation info available
Quintanar L
No affiliation info available
Grande-Aztatzi R
No affiliation info available
Mineva T
No affiliation info available
Goursot A
No affiliation info available

MeSH

Amyloid beta-PeptidesCoordination ComplexesCopperElectron Spin Resonance SpectroscopyHumansHydrogen-Ion ConcentrationLigandsMolecular ConformationOxidation-ReductionOxygen

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25090035

Citation

Gomez-Castro, Carlos Z., et al. "Insights Into the Oxygen-based Ligand of the Low pH Component of the Cu(2+)-amyloid-β Complex." The Journal of Physical Chemistry. B, vol. 118, no. 34, 2014, pp. 10052-64.
Gomez-Castro CZ, Vela A, Quintanar L, et al. Insights into the oxygen-based ligand of the low pH component of the Cu(2+)-amyloid-β complex. J Phys Chem B. 2014;118(34):10052-64.
Gomez-Castro, C. Z., Vela, A., Quintanar, L., Grande-Aztatzi, R., Mineva, T., & Goursot, A. (2014). Insights into the oxygen-based ligand of the low pH component of the Cu(2+)-amyloid-β complex. The Journal of Physical Chemistry. B, 118(34), 10052-64. https://doi.org/10.1021/jp5047529
Gomez-Castro CZ, et al. Insights Into the Oxygen-based Ligand of the Low pH Component of the Cu(2+)-amyloid-β Complex. J Phys Chem B. 2014 Aug 28;118(34):10052-64. PubMed PMID: 25090035.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Insights into the oxygen-based ligand of the low pH component of the Cu(2+)-amyloid-β complex. AU - Gomez-Castro,Carlos Z, AU - Vela,Alberto, AU - Quintanar,Liliana, AU - Grande-Aztatzi,Rafael, AU - Mineva,Tzonka, AU - Goursot,Annick, Y1 - 2014/08/14/ PY - 2014/8/5/entrez PY - 2014/8/5/pubmed PY - 2015/5/13/medline SP - 10052 EP - 64 JF - The journal of physical chemistry. B JO - J Phys Chem B VL - 118 IS - 34 N2 - In spite of significant experimental effort dedicated to the study of Cu(2+) binding to the amyloid beta (Aβ) peptide, involved in Alzheimer's disease, the nature of the oxygen-based ligand in the low pH component of the Cu(2+)-Aβ(1-16) complex is still under debate. This study reports density-functional-theory-based calculations that explore the potential energy surface of Cu(2+) complexes including N and O ligands at the N-terminus of the Aβ peptide, with a focus on evaluating the role of Asp1 carboxylate in copper coordination. Model conformers including 3, 6, and 17 amino acids have been used to systematically study several aspects of the Cu(2+)-coordination such as the Asp1 side chain conformation, local peptide backbone geometry, electrostatic and/or hydrogen bond interactions, and number and availability of Cu(2+) ligands. Our results show that the Asp1 peptide carbonyl binds to Cu(2+) only if the coordination number is less than four. In contrast, if four ligands are available, the most stable structures include the Asp1 carboxylate in equatorial position instead of the Asp1 carbonyl group. The two lowest energy Cu(2+)-Aβ(1-17) models involve Asp1 COO(-), the N-terminus, and His6 and His14 as equatorial ligands, with either a carbonyl or a water molecule in the axial position. These models are in good agreement with experimental data reported for component I of the Cu(2+)-Aβ(1-16) complex, including EXAFS- and X-ray-derived Cu(2+)-ligand distances, Cu(2+) EPR parameters, and (14)N and (13)C superhyperfine couplings. Our results suggest that at low pH, Cu(2+)-Aβ species with Asp1 carboxylate equatorial coordination coexist with species coordinating the Asp1 carbonyl. Understanding the bonding mechanism in these species is relevant to gain a deeper insight on the molecular processes involving copper-amyloid-β complexes, such as aggregation and redox activity. SN - 1520-5207 UR - https://www.unboundmedicine.com/medline/citation/25090035/Insights_into_the_oxygen_based_ligand_of_the_low_pH_component_of_the_Cu_2+__amyloid_β_complex_ DB - PRIME DP - Unbound Medicine ER -