Amino acid substitutions [K16A] and [K28A] distinctly affect amyloid beta-protein oligomerization

摘要

Amyloid beta-protein (A beta) 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 beta 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 beta alloforms in the brain, A beta (40) and A beta (42), whereas the [K28A] substitution exerts only a moderate effect. Here, folding and oligomerization of [A16]A beta (40), [A28]A beta (40), [A16]A beta (42), and [A28]A beta (42) are examined by discrete molecular dynamics (DMD) combined with a four-bead implicit solvent force field, DMD4B-HYDRA, and compared to A beta (40) and A beta (42) oligomer formation. Our results show that both substitutions promote A beta (40) and A beta (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 beta-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 beta oligomers, then the observed substitution-specific structural changes in A beta (40) and A beta (42) oligomers are critical for understanding the structural basis of A beta oligomer toxicity and correct identification of therapeutic targets against AD.