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Rimantadine binds to and inhibits the influenza A M2 proton channel without enantiomeric specificity

Rimantadine binds to and inhibits the influenza A M2 proton channel without enantiomeric specificity
Rimantadine binds to and inhibits the influenza A M2 proton channel without enantiomeric specificity
The influenza A M2 wild-type (WT) proton channel is the target of the anti-influenza drug rimantadine. Rimantadine has two enantiomers, though most investigations into drug binding and inhibition have used a racemic mixture. Solid-state NMR experiments using the full length-M2 WT have shown significant spectral differences that were interpreted to indicate tighter binding for (R)- vs (S)-rimantadine. However, it was unclear if this correlates with a functional difference in drug binding and inhibition. Using X-ray crystallography, we have determined that both (R)- and (S)-rimantadine bind to the M2 WT pore with slight differences in the hydration of each enantiomer. However, this does not result in a difference in potency or binding kinetics, as shown by similar values for kon, koff, and Kd in electrophysiological assays and for EC50 values in cellular assays. We concluded that the slight differences in hydration for the (R)- and (S)-rimantadine enantiomers are not relevant to drug binding or channel inhibition. To further explore the effect of the hydration of the M2 pore on binding affinity, the water structure was evaluated by grand canonical ensemble molecular dynamics simulations as a function of the chemical potential of the water. Initially, the two layers of ordered water molecules between the bound drug and the channel’s gating His37 residues mask the drug’s chirality. As the chemical potential becomes more unfavorable, the drug translocates down to the lower water layer, and the interaction becomes more sensitive to chirality. These studies suggest the feasibility of displacing the upper water layer and specifically recognizing the lower water layers in novel drugs.
0006-2960
2471–2482
Thomaston, Jessica L.
74fefd7f-531c-4147-921b-9514afd46276
Samways, Marley, Luke
75cda5aa-31ef-4f62-9ea3-8655ea55d3fb
Konstantinidi, Athina
e248bc32-d02e-4102-ae12-63203d1fcce2
Ma, Chunlong
f196fcb3-ef87-4de7-964a-c40800edd741
Yanmei, Hu
53f12433-b9d5-4274-86e8-78c243f768a3
Bruce Macdonald, Hannah
8e3f96bf-6806-4dc9-bd25-5b7a5325c7a7
Wang, Jun
210c331a-8da1-44d8-993c-6436ab47b479
Essex, Jonathan W.
1f409cfe-6ba4-42e2-a0ab-a931826314b5
DeGrado, William F.
a2788bd1-9048-44b6-975e-b22266ec423c
Kolocouris, Antonios
9808dd86-369e-4792-aca8-bf79acce7909
Thomaston, Jessica L.
74fefd7f-531c-4147-921b-9514afd46276
Samways, Marley, Luke
75cda5aa-31ef-4f62-9ea3-8655ea55d3fb
Konstantinidi, Athina
e248bc32-d02e-4102-ae12-63203d1fcce2
Ma, Chunlong
f196fcb3-ef87-4de7-964a-c40800edd741
Yanmei, Hu
53f12433-b9d5-4274-86e8-78c243f768a3
Bruce Macdonald, Hannah
8e3f96bf-6806-4dc9-bd25-5b7a5325c7a7
Wang, Jun
210c331a-8da1-44d8-993c-6436ab47b479
Essex, Jonathan W.
1f409cfe-6ba4-42e2-a0ab-a931826314b5
DeGrado, William F.
a2788bd1-9048-44b6-975e-b22266ec423c
Kolocouris, Antonios
9808dd86-369e-4792-aca8-bf79acce7909

Thomaston, Jessica L., Samways, Marley, Luke, Konstantinidi, Athina, Ma, Chunlong, Yanmei, Hu, Bruce Macdonald, Hannah, Wang, Jun, Essex, Jonathan W., DeGrado, William F. and Kolocouris, Antonios (2021) Rimantadine binds to and inhibits the influenza A M2 proton channel without enantiomeric specificity. Biochemistry, 60 (32), 2471–2482. (doi:10.1021/acs.biochem.1c00437).

Record type: Article

Abstract

The influenza A M2 wild-type (WT) proton channel is the target of the anti-influenza drug rimantadine. Rimantadine has two enantiomers, though most investigations into drug binding and inhibition have used a racemic mixture. Solid-state NMR experiments using the full length-M2 WT have shown significant spectral differences that were interpreted to indicate tighter binding for (R)- vs (S)-rimantadine. However, it was unclear if this correlates with a functional difference in drug binding and inhibition. Using X-ray crystallography, we have determined that both (R)- and (S)-rimantadine bind to the M2 WT pore with slight differences in the hydration of each enantiomer. However, this does not result in a difference in potency or binding kinetics, as shown by similar values for kon, koff, and Kd in electrophysiological assays and for EC50 values in cellular assays. We concluded that the slight differences in hydration for the (R)- and (S)-rimantadine enantiomers are not relevant to drug binding or channel inhibition. To further explore the effect of the hydration of the M2 pore on binding affinity, the water structure was evaluated by grand canonical ensemble molecular dynamics simulations as a function of the chemical potential of the water. Initially, the two layers of ordered water molecules between the bound drug and the channel’s gating His37 residues mask the drug’s chirality. As the chemical potential becomes more unfavorable, the drug translocates down to the lower water layer, and the interaction becomes more sensitive to chirality. These studies suggest the feasibility of displacing the upper water layer and specifically recognizing the lower water layers in novel drugs.

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3rd revised ms - Accepted Manuscript
Restricted to Repository staff only until 17 August 2022.
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Accepted/In Press date: 3 August 2021
Published date: 17 August 2021

Identifiers

Local EPrints ID: 451141
URI: http://eprints.soton.ac.uk/id/eprint/451141
ISSN: 0006-2960
PURE UUID: 58f0408f-427c-4809-8cc6-25fc30dee69d
ORCID for Marley, Luke Samways: ORCID iD orcid.org/0000-0001-9431-8789
ORCID for Jonathan W. Essex: ORCID iD orcid.org/0000-0003-2639-2746

Catalogue record

Date deposited: 14 Sep 2021 15:15
Last modified: 26 Nov 2021 03:12

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Contributors

Author: Jessica L. Thomaston
Author: Marley, Luke Samways ORCID iD
Author: Athina Konstantinidi
Author: Chunlong Ma
Author: Hu Yanmei
Author: Hannah Bruce Macdonald
Author: Jun Wang
Author: William F. DeGrado
Author: Antonios Kolocouris

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