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The ubiquitous mutation from serine (WT) to asparagine at residue 31 (S31N) in the influenza A M2 channel renders it insensitive to amantadine (AMT) and rimantadine (RMT) block, but it is unknown whether the inhibition results from weak binding or incomplete block. Two-electrode voltage clamp (TEVC) of transfected Xenopus oocytes revealed that the M2 S31N channel is essentially fully blocked by AMT at 10 mM, demonstrating that, albeit weak, AMT binding in a channel results in complete block of its proton current. In contrast, RMT achieves only a modest degree of block in the M2 S31N channel at 1 mM, with very little increase in block at 10 mM, indicating that the RMT binding site in the channel saturates with only modest block. From exponential curve fits to families of proton current wash-in and wash-out traces, the association rate constant (k1) is somewhat decreased for both AMT and RMT in the S31N, but the dissociation rate constant (k2) is dramatically increased compared with WT. The potentials of mean force (PMF) from adaptive biasing force (ABF) molecular dynamics simulations predict that rate constants should be exquisitely sensitive to the charge state of the His37 selectivity filter of M2. With one exception out of eight cases, predictions from the simulations with one and three charged side chains bracket the experimental rate constants, as expected for the acidic bath used in the TEVC assay. From simulations, the weak binding can be accounted for by changes in the potentials of mean force, but the partial block by RMT remains unexplained.
Alhadeff,
Computational and experimental analysis of drug binding to the Influenza M2 channel.
2014, Pubmed
Alhadeff,
Computational and experimental analysis of drug binding to the Influenza M2 channel.
2014,
Pubmed
Brooks,
CHARMM: the biomolecular simulation program.
2009,
Pubmed
Cady,
Structure of the amantadine binding site of influenza M2 proton channels in lipid bilayers.
2010,
Pubmed
Cady,
Specific binding of adamantane drugs and direction of their polar amines in the pore of the influenza M2 transmembrane domain in lipid bilayers and dodecylphosphocholine micelles determined by NMR spectroscopy.
2011,
Pubmed
Darve,
Adaptive biasing force method for scalar and vector free energy calculations.
2008,
Pubmed
Drakopoulos,
Unraveling the Binding, Proton Blockage, and Inhibition of Influenza M2 WT and S31N by Rimantadine Variants.
2018,
Pubmed
Drakopoulos,
Affinity of Rimantadine Enantiomers against Influenza A/M2 Protein Revisited.
2017,
Pubmed
Gleed,
Resistance-Mutation (N31) Effects on Drug Orientation and Channel Hydration in Amantadine-Bound Influenza A M2.
2015,
Pubmed
Gleed,
Why bound amantadine fails to inhibit proton conductance according to simulations of the drug-resistant influenza A M2 (S31N).
2015,
Pubmed
Hu,
An M2-V27A channel blocker demonstrates potent in vitro and in vivo antiviral activities against amantadine-sensitive and -resistant influenza A viruses.
2017,
Pubmed
Hu,
Histidines, heart of the hydrogen ion channel from influenza A virus: toward an understanding of conductance and proton selectivity.
2006,
Pubmed
Hu,
NMR detection of pH-dependent histidine-water proton exchange reveals the conduction mechanism of a transmembrane proton channel.
2012,
Pubmed
Jo,
CHARMM-GUI: a web-based graphical user interface for CHARMM.
2008,
Pubmed
Liao,
The influenza m2 cytoplasmic tail changes the proton-exchange equilibria and the backbone conformation of the transmembrane histidine residue to facilitate proton conduction.
2015,
Pubmed
Mandala,
Structural Basis for Asymmetric Conductance of the Influenza M2 Proton Channel Investigated by Solid-State NMR Spectroscopy.
2017,
Pubmed
Martin,
Comparative analysis of nucleotide translocation through protein nanopores using steered molecular dynamics and an adaptive biasing force.
2014,
Pubmed
Phillips,
Scalable molecular dynamics with NAMD.
2005,
Pubmed
Pinto,
A functionally defined model for the M2 proton channel of influenza A virus suggests a mechanism for its ion selectivity.
1997,
Pubmed
,
Xenbase
Sansom,
The influenza A virus M2 channel: a molecular modeling and simulation study.
1997,
Pubmed
Sharma,
Insight into the mechanism of the influenza A proton channel from a structure in a lipid bilayer.
2010,
Pubmed
Smondyrev,
Molecular dynamics simulation of proton transport through the influenza A virus M2 channel.
2002,
Pubmed
Tzitzoglaki,
Chemical Probes for Blocking of Influenza A M2 Wild-type and S31N Channels.
2020,
Pubmed
Wang,
Ion channel activity of influenza A virus M2 protein: characterization of the amantadine block.
1993,
Pubmed
,
Xenbase
Williams,
pH-dependent conformation, dynamics, and aromatic interaction of the gating tryptophan residue of the influenza M2 proton channel from solid-state NMR.
2013,
Pubmed
Williams,
Drug-induced conformational and dynamical changes of the S31N mutant of the influenza M2 proton channel investigated by solid-state NMR.
2013,
Pubmed
Wu,
A computational study of the closed and open states of the influenza a M2 proton channel.
2005,
Pubmed
