Molecular insight into the inhibition mechanism of cyrtominetin to α-hemolysin by molecular dynamics simulation

The protein α-hemolysin (α-HL) is a self-assembling exotoxin that binds to the membrane of a susceptible host cell. In this paper, experimental studies show that cyrtominetin (CTM) can inhibit the hemolytic activity of α-HL. To understand how CTM can affect hemolytic activity, molecular dynamics simulations were carried out for α-HL–CTM complex and these results were compared with the crystal structure of monomeric α-HL. With this approach, the analysis revealed that the inhibition of CTM involves CTM directly binding to α-HL. Due to the binding of CTM, the conformation of the critical “Loop” region was restrained. This mechanism was confirmed by the experimental data. These findings indicate that CTM hinders the lysis activity of α-HL through a novel mechanism.

Due to the binding of CTM, the conformation of the critical “Loop” region was restrained, which resulted in the inhibition of hemolytic activity.Figure optionsDownload as PowerPoint slideHighlights
► α-Hemolysin forms a membrane-inserted heptamer on the membrane of host cells.
►  Cyrtominetin can inhibit the hemolytic activity of α-HL.
►  By the binding of CTM, the conformational transition of the loop was blocked.
►  The restraint of the loop conformation resulted in the inhibition of α-HL activity.