title: Impact of Cu(II) Binding on Structures and Dynamics of Aβ42Monomer and Dimer: Molecular Dynamics Study.
abstract: The classical force field, which is compatible with the Amber force field 99SB, has been obtained for the interaction of Cu(II) with monomer and dimers of amyloid-β peptides using the coordination where Cu(II) is bound to His6, His13 (or His14), and Asp1 with distorted planar geometry. The newly developed force field and molecular dynamics simulation were employed to study the impact of Cu(II) binding on structures and dynamics of Aβ42monomer and dimers. It was shown that in the presence of Cu(II) the β content of monomer is reduced substantially compared with the wild-type Aβ42suggesting that, in accord with experiments, metal ions facilitate formation of amorphous aggregates rather than amyloid fibrils with cross-β structures. In addition, one possible mechanism for amorphous assembly is that the Asp23-Lys28 salt bridge, which plays a crucial role in β sheet formation, becomes more flexible upon copper ion binding to the Aβ N-terminus. The simulation of dimers was conducted with the Cu(II)/Aβ stoichiometric ratios of 1:1 and 1:2. For the 1:1 ratio Cu(II) delays the Aβ dimerization process as observed in a number of experiments. The mechanism underlying this phenomenon is associated with slow formation of interchain salt bridges in dimer as well as with decreased hydrophobicity of monomer upon Cu-binding.
authors.affiliation: Institute of Physics, Polish Academy of Sciences , Al. Lotnikow 32/46, 02-668 Warsaw, Poland.|Institute for Computational Science and Technology, Quang Trung Software City , Tan Chanh Hiep Ward, District 12, Ho Chi Minh City, Vietnam.
authors.forename: Pham Dinh Quoc
authors.initials: PD
authors.lastname: Huy
authors.affiliation: Institute for Computational Science and Technology, Quang Trung Software City , Tan Chanh Hiep Ward, District 12, Ho Chi Minh City, Vietnam.|Department of Chemistry, Nagoya University , Nagoya 464-8602, Japan.
authors.forename: Quan Van
authors.initials: QV
authors.lastname: Vuong
authors.affiliation: National Research Council of Italy CNR , Institute for Chemistry of Organometallic Compounds ICCOM, 50019 Florence, Italy.|Italian Institute for Nuclear Physics INFN , Section of Roma-Tor Vergata, 50019 Florence, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: La Penna
authors.affiliation: Biometals and Biological Chemistry, Institute of Chemistry, University of Strasbourg , 4 rue B. Pascal, 67081 Strasbourg, France.
authors.forename: Peter
authors.initials: P
authors.lastname: Faller
authors.affiliation: Institute of Physics, Polish Academy of Sciences , Al. Lotnikow 32/46, 02-668 Warsaw, Poland.
authors.forename: Mai Suan
authors.initials: MS
authors.lastname: Li
mesh_terms: D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D003300:Copper / Q000737:chemistry / Q000378:metabolism*; D004548:Elasticity; D057927:Hydrophobic and Hydrophilic Interactions; D056004:Molecular Dynamics Simulation; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D066329:Protein Aggregates; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D055672:Static Electricity
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D066329:Protein Aggregates; C075222:amyloid beta-protein (1-42); D003300:Copper
keywords: Alzheimer’s disease; Amyloid-β aggregation; Aβ−Cu interaction; amyloid-β peptide; copper binding to amyloid-β; copper ions; fibril formation; metal ions; protein aggregation