A Computational Study of Amyloid β-Protein Assembly in Crowded Environments

Abstract

Alzheimer's disease is strongly associated with aberrant amyloid β-protein (Aβ) assembly into heterogeneous, metastable oligomeric assemblies with structures that have not been experimentally characterized yet. The 40 and 42 amino acids long Aβ40 and Aβ42 are the two predominant Aβ alloforms in the brain. Whereas Aβ40 and Aβ42 oligomer formation from monomeric state is still inaccessible to fully atomistic explicit-solvent molecular dynamics, Aβ40 and Aβ42 oligomers were structurally characterized using discrete molecular dynamics (DMD) and an intermediate-resolution protein model within the DMD4B-HYDRA implicit solvent force field, and the corresponding oligomer size distributions well matched the available in vitro data. In vivo, however, Aβ coexists with other biomolecules in a rather crowded environment. To understand the effect of crowding on Aβ oligomer formation, we used the DMD4B-HYDRA force field and added to an ensemble of 32 monomeric Aβ40 or Aβ42 peptides inert spherical “crowders” with a diameter of 0.5 nm at various concentrations to examine their effect on Aβ40 and Aβ42 oligomerization pathways. Our results show that crowding shifts oligomer size distributions towards smaller oligomer sizes and increases solubility of both peptides in a concentration-dependent way. The effect is stronger for Aβ42, where crowding abolishes the multimodal character of the oligomer size distribution. Our structural analysis revealed that the stability of larger oligomers is compromised by effective osmotic pressure exerted by the crowders, resulting in an increased rate of assembly breakage. While in vivo crowding agents are not inert as the crowders in our study, we here reveal that crowding-induced osmotic pressure strongly affects protein assembly dynamics, which is of significance to the disease.