  Abeta is a disordered peptide central to Alzheimer's Disease. Aggregation of
Abeta has been widely explored, but its molecular crowding less so. The
synaptic cleft where Abeta locates only holds 60-70 water molecules along its
width. We subjected Abeta40 to 100 different simulations with variable water
cell size. We show that even for this disordered aggregation-prone peptide,
many properties are not cell-size dependent, i.e. a small cell is easily
justified. The radius of gyration, intra-peptide, and peptide-water hydrogen
bonds are well-sampled by short (50 ns) time scales at any cell size. Abeta is
mainly disordered with 0-30% alpha helix but undergoes consistent alpha-beta
transitions up to 14% strand in 5-10% of the simulations regardless of cell
size. The similar prevalence in long and short simulations indicate small
diffusion barriers for structural transitions in contrast to folded globular
proteins, which we suggest is a defining hallmark of intrinsically disordered
proteins. Importantly, the hydrophobic surface increases significantly in small
cells (confidence level 95%, two-tailed t-test), as does the variation in
exposure and backbone conformations (>40% and >27% increased standard
deviations). Whereas hydrophilic exposure dominates hydrophobic exposure in
large cells, this tendency breaks down at low water concentration. We interpret
these findings as a concentration-dependent hydrophobic effect, with the small
water layer unable to keep the protein unexposed, an effect mainly caused by
the layered water-water interactions, not by the peptide dynamics. The exposure
correlates with radius of gyration (R2 0.35-0.50) and could be important in
crowded environments, e.g. the synaptic cleft.
