cn6b00357_si_001.pdf (364.54 kB)
Alzheimer’s Protective Cross-Interaction between Wild-Type and A2T Variants Alters Aβ42 Dimer Structure
journal contribution
posted on 2016-11-07, 00:00 authored by Payel Das, Anita R. Chacko, Georges BelfortWhole
genome sequencing has recently revealed the protective effect
of a single A2T mutation in heterozygous carriers against Alzheimer’s
disease (AD) and age-related cognitive decline. The impact of the
protective cross-interaction between the wild-type (WT) and A2T variants
on the dimer structure is therefore of high interest, as the Aβ
dimers are the smallest known neurotoxic species. Toward this goal,
extensive atomistic replica exchange molecular dynamics simulations
of the solvated WT homo- and A2T hetero- Aβ1–42 dimers have been performed, resulting into a total of 51 μs
of sampling for each system. Weakening of a set of transient, intrachain
contacts formed between the central and C-terminal hydrophobic residues
is observed in the heterodimeric system. The majority of the heterodimers
with reduced interaction between central and C-terminal regions lack
any significant secondary structure and display a weak interchain
interface. Interestingly, the A2T N-terminus, particularly residue
F4, is frequently engaged in tertiary and quaternary interactions
with central and C-terminal hydrophobic residues in those distinct
structures, leading to hydrophobic burial. This atypical involvement
of the N-terminus within A2T heterodimer revealed in our simulations
implies possible interference on Aβ42 aggregation
and toxic oligomer formation, which is consistent with experiments.
In conclusion, the present study provides detailed structural insights
onto A2T Aβ42 heterodimer, which might provide molecular
insights onto the AD protective effect of the A2T mutation in the
heterozygous state.