title: Amino acid substitutions [K16A] and [K28A] distinctly affect amyloid β-protein oligomerization.
abstract: Amyloid β-protein (A β) assembles into oligomers that play a seminal role in Alzheimer's disease (AD), a leading cause of dementia among the elderly. Despite undisputed importance of A β oligomers, their structure and the basis of their toxicity remain elusive. Previous experimental studies revealed that the [K16A] substitution strongly inhibits toxicity of the two predominant A β alloforms in the brain, A β 40 and A β 42, whereas the [K28A] substitution exerts only a moderate effect. Here, folding and oligomerization of [A16]A β 40, [A28]A β 40, [A16]A β 42, and [A28]A β 42 are examined by discrete molecular dynamics (DMD) combined with a four-bead implicit solvent force field, DMD4B-HYDRA, and compared to A β 40 and A β 42 oligomer formation. Our results show that both substitutions promote A β 40 and A β 42 oligomerization and that structural changes to oligomers are substitution- and alloform-specific. The [K28A] substitution increases solvent-accessible surface area of hydrophobic residues and the intrapeptide N-to-C terminal distance within oligomers more than the [K16A] substitution. The [K16A] substitution decreases the overall β-strand content, whereas the [K28A] substitution exerts only a modest change. Substitution-specific tertiary and quaternary structure changes indicate that the [K16A] substitution induces formation of more compact oligomers than the [K28A] substitution. If the structure-function paradigm applies to A β oligomers, then the observed substitution-specific structural changes in A β 40 and A β 42 oligomers are critical for understanding the structural basis of A β oligomer toxicity and correct identification of therapeutic targets against AD.
authors.affiliation: Faculty of Mathematics and Physics, Jadranska ulica 19, 1000, Ljubljana, Slovenia.
authors.forename: Matjaž
authors.initials: M
authors.lastname: Žganec
authors.affiliation: Drexel University, 3141 Chestnut St., Philadelphia, PA, 19104, USA.|University of Colorado at Boulder, UCB 391, Boulder, CO, 80309, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Kruczek
authors.affiliation: Faculty of Mathematics and Physics, Jadranska ulica 19, 1000, Ljubljana, Slovenia. brigita@drexel.edu.|Drexel University, 3141 Chestnut St., Philadelphia, PA, 19104, USA. brigita@drexel.edu.
authors.forename: Brigita
authors.initials: B
authors.lastname: Urbanc
mesh_terms: D019943:Amino Acid Substitution; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000235:genetics*; D006801:Humans; D056004:Molecular Dynamics Simulation; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics*; D017510:Protein Folding; D055503:Protein Multimerization / Q000235:genetics*; D020836:Protein Structure, Quaternary; D013816:Thermodynamics
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)
keywords: Alzheimer’s disease; Amyloid β-protein; Oligomer structure; Oligomerization; Protein folding and assembly; Structure-toxicity relationship