LAUSR

Abstract Previous studies have indicated that 5-hydroxycyclopenicillone (HCP), an active compound derived from marine sponge, could inhibit oligomerization of amyloid β-protein (Aβ). However, the molecular basis for the interaction between HCP and Aβ remains unclear. Herein, all-atom molecular dynamics (MD) simulations were used to explore the conformational conversion of an Aβ40 monomer at different concentrations (0-40 mM) of HCP at the atomic level. It is confirmed that the conformational transition of the Aβ40 monomer is prevented by HCP in a concentration-dependent manner in silico. In 40 mM HCP solution, the initial α-helix-rich conformation of Aβ40 monomer is kept under the action of HCP. The intra-peptide hydrophobic collapse and D23-K28 salt bridge are prevented by HCP. Moreover, it is indicated that the non-polar binding energy dominates the binding between HCP and Aβ40 monomer as evaluated by molecular mechanics Poisson-Boltzmann surface area method. And, the residues of F4, Y10, V12, L17 and L34 in Aβ40 might contribute to the binding energy in HCP-Aβ40 complex. All these results elucidate the molecular mechanism underlying the inhibitory effects of HCP against the conformational transformation of Aβ40, providing a support that HCP may be developed as a potential anti-Aβ compound for the treatment of Aβ-related diseases. Communicated by Ramaswamy H. Sarma