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

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

Keywords:

• Amyloid-β peptide
• small molecular inhibitor
• molecular dynamics simulation

Disclosure statement

The authors declare no conflicts of interest.

Additional information

Funding

This work was funded by the National Natural Science Foundation of China (Grant Nos. 21908165, 21878234 and 21576199), the Natural Science Foundation of Tianjin from the Tianjin Municipal Science and Technology Commission (Contract No. 18JCZDJC33000), the project of Novel Coronavirus Prevention and Treatment of Tianjin University of Science & Technology (No. 2020STCV0018) and the Open Project Program of State Key Laboratory of Food Nutrition and Safety, Tianjin University of Science & Technology (No. SKLFNS-KF-201902).