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Microbiol Immunol. 2017 Dec 6. doi: 10.1111/1348-0421.12561. [Epub ahead of print]
Binding pathway analysis of influenza virus M2 channel blockers by metadynamics simulation.
Sakai Y1, Kawaguchi A1,2,3, Nagata K2, Hirokawa T3,4,5.
Author information
Abstract
M2 protein of influenza A virus is a proton channel spanning the viral envelope. This proton channel activity is required for uncoating of viral particles and equilibrating the pH across the trans-Golgi apparatus to prevent a conformational change of hemagglutinin. Amantadine is an anti-influenza A virus drug which inhibits M2 proton channel activity by binding to the channel pore, however, the majority of currently circulating influenza A viruses are amantadine-resistant. The most prevalent resistant mutation is a substitution from Ser31 to Asn31 in M2. To provide new approaches for the design of novel M2 channel blockers, further atomistic analysis of ligand-M2 complexes is needed. Here we examined the free energy profiles of the binding kinetics of M2 channel blockers by well-tempered metadynamics simulations. We found that amantadine first binds to Asp24 of S31 M2 and forms a metastable conformation. In contrast, the free energy profiles of adamantyl bromothiophene dual inhibitor with either S31 M2 or N31 M2 were a broad funnel-shaped curve, suggesting that adamantyl bromothiophene does not form metastable complexes with M2. The trajectory of well-tempered metadynamics simulations revealed that the steric hindrance between adamantyl bromothiophene and S31 M2 interrupts the formation of metastable conformation at Asp24, and a halogen bond between the bromine atom and N31 is responsible for pulling down the ligand to the channel pore of N31 M2 without metastable state. Based on these results, we propose binding pathways of M2 channel blockers to M2 for providing new approaches to design further M2 channel blockers.
PMID: 29210473 DOI: 10.1111/1348-0421.12561
Binding pathway analysis of influenza virus M2 channel blockers by metadynamics simulation.
Sakai Y1, Kawaguchi A1,2,3, Nagata K2, Hirokawa T3,4,5.
Author information
Abstract
M2 protein of influenza A virus is a proton channel spanning the viral envelope. This proton channel activity is required for uncoating of viral particles and equilibrating the pH across the trans-Golgi apparatus to prevent a conformational change of hemagglutinin. Amantadine is an anti-influenza A virus drug which inhibits M2 proton channel activity by binding to the channel pore, however, the majority of currently circulating influenza A viruses are amantadine-resistant. The most prevalent resistant mutation is a substitution from Ser31 to Asn31 in M2. To provide new approaches for the design of novel M2 channel blockers, further atomistic analysis of ligand-M2 complexes is needed. Here we examined the free energy profiles of the binding kinetics of M2 channel blockers by well-tempered metadynamics simulations. We found that amantadine first binds to Asp24 of S31 M2 and forms a metastable conformation. In contrast, the free energy profiles of adamantyl bromothiophene dual inhibitor with either S31 M2 or N31 M2 were a broad funnel-shaped curve, suggesting that adamantyl bromothiophene does not form metastable complexes with M2. The trajectory of well-tempered metadynamics simulations revealed that the steric hindrance between adamantyl bromothiophene and S31 M2 interrupts the formation of metastable conformation at Asp24, and a halogen bond between the bromine atom and N31 is responsible for pulling down the ligand to the channel pore of N31 M2 without metastable state. Based on these results, we propose binding pathways of M2 channel blockers to M2 for providing new approaches to design further M2 channel blockers.
PMID: 29210473 DOI: 10.1111/1348-0421.12561