2.1 Monomer
The current experimental view we have for Aβ40 and Aβ42 monomers is that
they lack stable secondary and tertiary structures and have flat free
energy surfaces.17 The monomers consist of a
heterogeneous ensemble of random coil states with little α-helix and
β-strand character. Both extended and compact conformations were
obtained by SOP-IDP coarse-grained Langevin dynamics simulations at 300
K,18 all-atom metadynamics simulations at 350 K using
CHARMM22-TIP3P force field,19 and atomistic MD
simulations at 300 K using the AMBER99SB-disp12 and
CHARMM36m-TIP3P modified20 force fields.
Small helical contents in monomer were evidenced by many theoretical
studies. Metadynamics at 350 K applied to Aβ40 monomer predicted high
energy states with α-helix at residues 21-26 and
30-37.19 Aβ42 conformations with α-helix content
spanning residues 10-20 were predicted by the Folding@home approach
using thousands of MD simulations with the AMBER99sb-TIP3P force
field,21 and by multiple-reservoir replica exchange
simulations with the AMBER99sb/TIP4P-Ew force field.22Partially folded α-helical structures spanning the CHC (central
hydrophobic core, residues 17-21) and residues 30-38 of Aβ42 were
reported by MD simulations and Hamiltonian replica exchange with solute
scaling.23 A short helix covering residues 17-23 was
also reported for Aβ40 monomer using a predictive coarse-grained force
field.24
Transient helical conformations were also evidenced experimentally. They
were reported by a SERS (surface enhanced Raman spectroscopy) study on
Aβ40 monomer between pH 5.5 and 10.5.25 A nuclear
magnetic resonance (NMR) structure of Aβ40 monomer reported on the
formation of a 3-10 helix spanning residues 13-23 at pH 7.3 at 50mM
NaCl.26 Aβ42 monomer was found essentially disordered
but displays α-helix spanning residues 15-24 and 29-35 in the presence
of micelles.7
Small β-strand contents were evidenced by circular dichroism (CD)
experiments17 and many simulations using atomistic or
coarse-grained models, suggesting notably the existence of multiple
transient β-hairpin conformations covering the CHC and the C-terminus
(30-42),7,27,28 and revealing the very low
probabilities of the aggregation-prone N* states with U-shaped or
S-shaped fibrillar conformations.18