Effects of Small Compounds on Structure of Amyloid-β_1-42 Monomer

Alzheimer’s disease is associated with deposits of Amyloid-β, an intrinsically disordered peptide. Molecular structure and aggregation rate of Aβ are observed to be significantly dependent on the properties of its aqueous environment. For example, NaCl is shown to accelerate Aβ fibril formation whereas 4-Aminophenol (4AP) and Inositol have been shown to reduce its aggregation rate. Despite many studies to investigate the effects of small molecules on aggregation of Aβ, its atomic interactions with small molecules that mediate various structures and behavior of this peptide are not well understood. To investigate Aβ molecular structures and to understand how Aβ properties are affected by compounds, we performed extensive Replica Exchange Molecular Dynamics (REMD) simulations on Aβ_1-42 monomer with explicit solvent and small molecules. Our research reveals that each molecule affects different regions of Aβ_1-42 and the peptide adopts distinguished structures compared to control system. Specifically, we observe that NaCl increases contact among residues K16-E22 and V38-I41 while 4AP increases K16-E22 and N27-G37 contacts and Inositol mainly disrupts the intrapeptide contacts. Effects of compounds on structural and physical properties of Aβ_1-42 monomer will also be discussed.