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