Revisiting Cu(II) Bound Amyloid-β40 and Amyloid-β42 Peptides: Varying Coordination Chemistries

Yıl 2018, Cilt: 5 Sayı: 3, 981 - 1008, 01.09.2018

Orkid Coskuner-weber

https://doi.org/10.18596/jotcsa.424144

Cited By: 6

Öz

Metal ions and intrinsically disordered peptides amyloid-β40
and amyloid-β42 are at the center of Alzheimer´s disease pathology. Divalent
copper ion binds to amyloid-β40 and amyloid-β42 peptides with varying
coordination chemistries. Experiments face challenges in the measurements of
divalent copper ion bound monomeric amyloid-β40 and amyloid-β42 in an aqueous
solution medium because of fast conformational changes, rapid aggregation
processes and solvent effects. Theoretical studies complement experiments and
provide insights at the atomic and molecular levels with dynamics. However,
until recently, potential functions for simulating divalent copper ion bound
amyloid-β40 and amyloid-β42 peptides with varying coordination chemistries were
lacking. Using new potential functions that were developed for divalent copper
centers, Cu(II), including three histidine residues and an oxygen-ligated amino
acid residue, the structures and thermodynamic properties of Cu(II)-bound
amyloid-β40 and amyloid-β42 peptides in an aqueous solution medium were
studied. For these purposes, extensive first principles calculations and
replica exchange molecular dynamics simulations were conducted. In this study,
the secondary and tertiary structural properties, conformational Gibbs free
energy values, potential of mean force surfaces, salt bridges and aggregation
propensities of aqueous Cu(II)-bound amyloid-β40 and amyloid-β42 peptides are
presented. Different than previous findings in the literature, results clearly
show that the coordination chemistry variations impact the structural and
thermodynamic properties of divalent Cu(II) bound amyloid-β alloforms in water.
Specificities about these differences are revealed in this study at the atomic
level with dynamics. Results presented herein are the first to offer a
comparison of the monomeric Cu(II)-bound amyloid-β40 and amyloid-β42 peptides
with varying coordination chemistries using bonded model potential functions.

Anahtar Kelimeler

Copper, amyloid-β, coordination chemistry, replica exchange molecular dynamics simulations, Alzheimer's disease

Kaynakça

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