Limits...
Molecular modeling reveals the novel inhibition mechanism and binding mode of three natural compounds to staphylococcal α-hemolysin.

Qiu J, Wang D, Zhang Y, Dong J, Wang J, Niu X - PLoS ONE (2013)

Bottom Line: This was completed using conventional Molecular Dynamics (MD) simulations.This novel inhibition mechanism has been confirmed by both the steered MD simulations and the experimental data obtained from a deoxycholate-induced oligomerization assay.This study can facilitate the design of new antibacterial drugs against S. aureus.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Zoonosis, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, China.

ABSTRACT
α-Hemolysin (α-HL) is a self-assembling, channel-forming toxin that is produced as a soluble monomer by Staphylococcus aureus strains. Until now, α-HL has been a significant virulence target for the treatment of S. aureus infection. In our previous report, we demonstrated that some natural compounds could bind to α-HL. Due to the binding of those compounds, the conformational transition of α-HL from the monomer to the oligomer was blocked, which resulted in inhibition of the hemolytic activity of α-HL. However, these results have not indicated how the binding of the α-HL inhibitors influence the conformational transition of the whole protein during the oligomerization process. In this study, we found that three natural compounds, Oroxylin A 7-O-glucuronide (OLG), Oroxin A (ORA), and Oroxin B (ORB), when inhibiting the hemolytic activity of α-HL, could bind to the "stem" region of α-HL. This was completed using conventional Molecular Dynamics (MD) simulations. By interacting with the novel binding sites of α-HL, the ligands could form strong interactions with both sides of the binding cavity. The results of the principal component analysis (PCA) indicated that because of the inhibitors that bind to the "stem" region of α-HL, the conformational transition of α-HL from the monomer to the oligomer was restricted. This caused the inhibition of the hemolytic activity of α-HL. This novel inhibition mechanism has been confirmed by both the steered MD simulations and the experimental data obtained from a deoxycholate-induced oligomerization assay. This study can facilitate the design of new antibacterial drugs against S. aureus.

Show MeSH

Related in: MedlinePlus

Free energy profiles determined for OLG, ORA and ORB binding with α-HL.The reaction coordinate was defined as the distance between the center of mass of all of the atoms of OLG, ORA or ORB and the center of mass of all of the atoms that belong to α-HL.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3842302&req=5

pone-0080197-g008: Free energy profiles determined for OLG, ORA and ORB binding with α-HL.The reaction coordinate was defined as the distance between the center of mass of all of the atoms of OLG, ORA or ORB and the center of mass of all of the atoms that belong to α-HL.

Mentions: To address the above-mentioned hypothesis, we determined the performed potential of mean force (PMF) for each of the three binding complexes, including α-HL-OLG, α-HL-ORA, and α-HL-ORB, based on the data collected from the umbrella-sampling MD simulations. The performed potential of mean force (PMF) results depicted in Figure 8 are based on the MD simulations for 10 ns windows.


Molecular modeling reveals the novel inhibition mechanism and binding mode of three natural compounds to staphylococcal α-hemolysin.

Qiu J, Wang D, Zhang Y, Dong J, Wang J, Niu X - PLoS ONE (2013)

Free energy profiles determined for OLG, ORA and ORB binding with α-HL.The reaction coordinate was defined as the distance between the center of mass of all of the atoms of OLG, ORA or ORB and the center of mass of all of the atoms that belong to α-HL.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3842302&req=5

pone-0080197-g008: Free energy profiles determined for OLG, ORA and ORB binding with α-HL.The reaction coordinate was defined as the distance between the center of mass of all of the atoms of OLG, ORA or ORB and the center of mass of all of the atoms that belong to α-HL.
Mentions: To address the above-mentioned hypothesis, we determined the performed potential of mean force (PMF) for each of the three binding complexes, including α-HL-OLG, α-HL-ORA, and α-HL-ORB, based on the data collected from the umbrella-sampling MD simulations. The performed potential of mean force (PMF) results depicted in Figure 8 are based on the MD simulations for 10 ns windows.

Bottom Line: This was completed using conventional Molecular Dynamics (MD) simulations.This novel inhibition mechanism has been confirmed by both the steered MD simulations and the experimental data obtained from a deoxycholate-induced oligomerization assay.This study can facilitate the design of new antibacterial drugs against S. aureus.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Zoonosis, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, China.

ABSTRACT
α-Hemolysin (α-HL) is a self-assembling, channel-forming toxin that is produced as a soluble monomer by Staphylococcus aureus strains. Until now, α-HL has been a significant virulence target for the treatment of S. aureus infection. In our previous report, we demonstrated that some natural compounds could bind to α-HL. Due to the binding of those compounds, the conformational transition of α-HL from the monomer to the oligomer was blocked, which resulted in inhibition of the hemolytic activity of α-HL. However, these results have not indicated how the binding of the α-HL inhibitors influence the conformational transition of the whole protein during the oligomerization process. In this study, we found that three natural compounds, Oroxylin A 7-O-glucuronide (OLG), Oroxin A (ORA), and Oroxin B (ORB), when inhibiting the hemolytic activity of α-HL, could bind to the "stem" region of α-HL. This was completed using conventional Molecular Dynamics (MD) simulations. By interacting with the novel binding sites of α-HL, the ligands could form strong interactions with both sides of the binding cavity. The results of the principal component analysis (PCA) indicated that because of the inhibitors that bind to the "stem" region of α-HL, the conformational transition of α-HL from the monomer to the oligomer was restricted. This caused the inhibition of the hemolytic activity of α-HL. This novel inhibition mechanism has been confirmed by both the steered MD simulations and the experimental data obtained from a deoxycholate-induced oligomerization assay. This study can facilitate the design of new antibacterial drugs against S. aureus.

Show MeSH
Related in: MedlinePlus