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Why bound amantadine fails to inhibit proton conductance according to simulations of the drug-resistant influenza A M2 (S31N).

Gleed ML, Busath DD - J Phys Chem B (2014)

Bottom Line: After evaluation of 13 published M2 structures, a solid-state NMR structure with amantadine bound was selected for simulations, an S31N mutant structure was developed and equilibrated, and the native and mutant structures were used to determine the binding behavior of amantadine and the dynamics of water in the two channels.Amantadine is stable in the plugging region of wild-type M2, with the adamantane in contact with the Val27 side chains, while amantadine in S31N M2 has more variable movement and orientation, and spontaneously moves lower into the central cavity of the channel.In this configuration, water surrounds the drug and can easily transport protons past it, so the drug binds without blocking proton transport in the S31N M2 channel.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Developmental Biology, Brigham Young University , Provo, Utah 84602, United States.

ABSTRACT
The mechanisms responsible for drug resistance in the Asn31 variant of the M2 protein of influenza A are not well understood. Molecular dynamics simulations were performed on wild-type (Ser31) and S31N influenza A M2 in the homotetramer configuration. After evaluation of 13 published M2 structures, a solid-state NMR structure with amantadine bound was selected for simulations, an S31N mutant structure was developed and equilibrated, and the native and mutant structures were used to determine the binding behavior of amantadine and the dynamics of water in the two channels. Amantadine is stable in the plugging region of wild-type M2, with the adamantane in contact with the Val27 side chains, while amantadine in S31N M2 has more variable movement and orientation, and spontaneously moves lower into the central cavity of the channel. Free energy profiles from umbrella sampling support this observation. In this configuration, water surrounds the drug and can easily transport protons past it, so the drug binds without blocking proton transport in the S31N M2 channel.

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Free energy landscapes of amantadine in WT (blue) and S31N (red)M2 channels. The free energy minimum of each channel was set to 0kcal/mol. One standard deviation between runs is shown in dotted linesof the corresponding color above and below each trace. Gly34 and Ser/Asn31mean α-carbon positions (black arrowheads) are shown for referencefrom left to right, respectively.
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fig6: Free energy landscapes of amantadine in WT (blue) and S31N (red)M2 channels. The free energy minimum of each channel was set to 0kcal/mol. One standard deviation between runs is shown in dotted linesof the corresponding color above and below each trace. Gly34 and Ser/Asn31mean α-carbon positions (black arrowheads) are shown for referencefrom left to right, respectively.

Mentions: To investigatethe reasons behind the difference in binding behavior of amantadineto WT and S31N M2, free energy profiles of amantadine through eachchannel were computed via umbrella sampling. The potential of meanforce (PMF) for each channel was calculated by analyzing the positionof the adamantane cage of amantadine, the center of mass of whichwas constrained to specific z coordinates at 0.25Å intervals, in independent simulations (Figure 6).


Why bound amantadine fails to inhibit proton conductance according to simulations of the drug-resistant influenza A M2 (S31N).

Gleed ML, Busath DD - J Phys Chem B (2014)

Free energy landscapes of amantadine in WT (blue) and S31N (red)M2 channels. The free energy minimum of each channel was set to 0kcal/mol. One standard deviation between runs is shown in dotted linesof the corresponding color above and below each trace. Gly34 and Ser/Asn31mean α-carbon positions (black arrowheads) are shown for referencefrom left to right, respectively.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4306489&req=5

fig6: Free energy landscapes of amantadine in WT (blue) and S31N (red)M2 channels. The free energy minimum of each channel was set to 0kcal/mol. One standard deviation between runs is shown in dotted linesof the corresponding color above and below each trace. Gly34 and Ser/Asn31mean α-carbon positions (black arrowheads) are shown for referencefrom left to right, respectively.
Mentions: To investigatethe reasons behind the difference in binding behavior of amantadineto WT and S31N M2, free energy profiles of amantadine through eachchannel were computed via umbrella sampling. The potential of meanforce (PMF) for each channel was calculated by analyzing the positionof the adamantane cage of amantadine, the center of mass of whichwas constrained to specific z coordinates at 0.25Å intervals, in independent simulations (Figure 6).

Bottom Line: After evaluation of 13 published M2 structures, a solid-state NMR structure with amantadine bound was selected for simulations, an S31N mutant structure was developed and equilibrated, and the native and mutant structures were used to determine the binding behavior of amantadine and the dynamics of water in the two channels.Amantadine is stable in the plugging region of wild-type M2, with the adamantane in contact with the Val27 side chains, while amantadine in S31N M2 has more variable movement and orientation, and spontaneously moves lower into the central cavity of the channel.In this configuration, water surrounds the drug and can easily transport protons past it, so the drug binds without blocking proton transport in the S31N M2 channel.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Developmental Biology, Brigham Young University , Provo, Utah 84602, United States.

ABSTRACT
The mechanisms responsible for drug resistance in the Asn31 variant of the M2 protein of influenza A are not well understood. Molecular dynamics simulations were performed on wild-type (Ser31) and S31N influenza A M2 in the homotetramer configuration. After evaluation of 13 published M2 structures, a solid-state NMR structure with amantadine bound was selected for simulations, an S31N mutant structure was developed and equilibrated, and the native and mutant structures were used to determine the binding behavior of amantadine and the dynamics of water in the two channels. Amantadine is stable in the plugging region of wild-type M2, with the adamantane in contact with the Val27 side chains, while amantadine in S31N M2 has more variable movement and orientation, and spontaneously moves lower into the central cavity of the channel. Free energy profiles from umbrella sampling support this observation. In this configuration, water surrounds the drug and can easily transport protons past it, so the drug binds without blocking proton transport in the S31N M2 channel.

Show MeSH
Related in: MedlinePlus