Molecular basis for the inhibitory effects of 5-hydroxycyclopenicillone on the conformational transition of Aβ40 monomer

Previous studies have indicated that 5-hydroxycyclopenicillone (HCP), an active compound derived from marine sponge, could inhibit oligomerization of amyloid beta-protein (A beta). However, the molecular basis for the interaction between HCP and A beta remains unclear. Herein, all-atom molecular dynamics (MD) simulations were used to explore the conformational conversion of an A beta(40) monomer at different concentrations (0-40 mM) of HCP at the atomic level. It is confirmed that the conformational transition of the A beta(40) monomer is prevented by HCP in a concentration-dependent mannerin silico. In 40 mM HCP solution, the initial alpha-helix-rich conformation of A beta(40) 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 A beta(40) monomer as evaluated by molecular mechanics Poisson-Boltzmann surface area method. And, the residues of F4, Y10, V12, L17 and L34 in A beta(40) might contribute to the binding energy in HCP-A beta(40) complex. All these results elucidate the molecular mechanism underlying the inhibitory effects of HCP against the conformational transformation of A beta(40), providing a support that HCP may be developed as a potential anti-A beta compound for the treatment of A beta-related diseases.

Automated summary

This study utilized molecular dynamics simulations to investigate the inhibitory effects of HCP on the conformational transformation of A beta. The results showed that HCP can prevent the conformational transition of A beta monomers in a concentration-dependent manner, suggesting its potential as an anti-A beta compound.