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JOURNAL ARTICLE
RESEARCH SUPPORT, NON-U.S. GOV'T
RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
Amino acid substitutions [K16A] and [K28A] distinctly affect amyloid β-protein oligomerization.
Journal of Biological Physics 2016 June
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.
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