The Interplay of Functional Tuning, Drug Resistance, and Thermodynamic Stability in the Evolution of the M2 Proton Channel from the Influenza A Virus

We explore the interplay between amino acid sequence, thermodynamic stability, and functional fitness in the M2 proton channel of influenza A virus. Electrophysiological measurements show that drug-resistant mutations have minimal effects on M2’s specific activity, and suggest that resistance is ach...

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Bibliographic Details
Published in:Structure (London) 2008-07, Vol.16 (7), p.1067-1076
Main Authors: Stouffer, Amanda L., Ma, Chunlong, Cristian, Lidia, Ohigashi, Yuki, Lamb, Robert A., Lear, James D., Pinto, Lawrence H., DeGrado, William F.
Format: Article
Language:English
Subjects:
Amantadine - pharmacology
Amino Acid Sequence
Animals
Antiviral Agents - pharmacology
Cells, Cultured
Disulfides - chemistry
Drug Resistance, Viral - genetics
Evolution, Molecular
Influenza A virus
Ion Channels - chemistry
Ion Channels - genetics
Ion Channels - metabolism
Lipid Bilayers - chemistry
Micelles
MICROBIO
Models, Molecular
Molecular Sequence Data
Mutation
Patch-Clamp Techniques
Phospholipids - chemistry
PROTEINS
Protons
Thermodynamics
Viral Matrix Proteins - chemistry
Viral Matrix Proteins - genetics
Viral Matrix Proteins - metabolism
Xenopus laevis
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Summary:We explore the interplay between amino acid sequence, thermodynamic stability, and functional fitness in the M2 proton channel of influenza A virus. Electrophysiological measurements show that drug-resistant mutations have minimal effects on M2’s specific activity, and suggest that resistance is achieved by altering a binding site within the pore rather than a less direct allosteric mechanism. In parallel, we measure the effects of these mutations on the free energy of assembling the homotetrameric transmembrane pore from monomeric helices in micelles and bilayers. Although there is no simple correlation between the evolutionary fitness of the mutants and their stability, all variants formed more stable tetramers in bilayers, and the least-fit mutants showed the smallest increase in stability upon moving from a micelle to a bilayer environment. We speculate that the folding landscape of a micelle is rougher than that of a bilayer, and more accommodating of conformational variations in nonoptimized mutants.
ISSN:0969-2126
1878-4186
DOI:10.1016/j.str.2008.04.011