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Two studies published in Science in October 2010 examined how the influenza A M2 protein conducts protons and changes state. Both placed the channel’s histidine residues at the center of proton transport, but they offered different accounts of how the nearby tryptophan residue contributes. Their findings refined a mechanistic picture; they did not announce a new flu medicine or establish a complete, directly observed route for every proton.
What M2 does during influenza A infection
M2 is a proton channel embedded in the influenza A viral membrane. When a virus particle enters a host cell, it is taken into an acidic compartment called an endosome. M2 allows protons to flow into the virus, helping acidify its interior. That change helps viral components come apart so the viral genome can be released into the host cell.
Because M2 is important to this entry process, it has also been studied as a possible antiviral drug target. The 2010 papers focused on how the channel works at a molecular level, not on demonstrating a new treatment.
Why the two studies mattered
M2 is assembled from four protein subunits. In the channel’s membrane-spanning region, each subunit contributes a histidine at position 37, known as His37. These residues respond to pH and participate in proton transfer. The studies used solid-state nuclear magnetic resonance (NMR) and membrane-like systems to investigate the channel’s structure and motion.
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In her October 21, 2010 Chemistry World report, Hayley Bennett described the work as two complementary but not identical efforts: one emphasized direct NMR measurements on a shorter protein segment in a virus-envelope-mimicking membrane, while the other combined structural data from a larger construct with simulations to propose a more detailed transfer route. [Chemistry World, October 21, 2010]
How the Iowa State study explained proton movement
Fanghao Hu, Wenbin Luo, and Mei Hong studied His37 using solid-state NMR in a cholesterol-containing membrane designed to mimic the influenza virus envelope. They described a high-pH closed configuration and a low-pH conducting configuration. Their proposed mechanism has the His37 imidazole rings dynamically accepting and passing protons. In their interpretation, a ring-flip-assisted step that allows a histidine to lose a proton helps limit the rate of conduction.
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The NMR measurements supported a model of pH-dependent structure and dynamics; they did not film individual protons moving through the channel. The distinction matters: the proposed sequence of molecular events is an interpretation of the measurements, rather than a direct observation of every transfer.
Do these 3 things before closing this tab:
1Fix the driver behind crashes, sound loss and screen glitches2Repair Windows errors before they cause bigger problems3Scan for outdated or missing drivers - takes under a minuteThe authors presented their findings in “Mechanisms of Proton Conduction and Gating in Influenza M2 Proton Channels from Solid-State NMR.” [Science, October 22, 2010]
How the Florida State study added a different model
Mukesh Sharma, Myunggi Yi, Hao Dong, and colleagues used a larger M2 construct and structural data from a lipid bilayer, alongside simulations. Their work proposed a more detailed pathway involving water, His37, and Trp41, the tryptophan residue near the channel’s inner end. In this model, Trp41 helps shape or regulate the proton-transfer process.
The study and the Iowa State work agreed on the central importance of His37 but differed over how necessary Trp41 was to the mechanism. Florida State researcher Huan-Xiang Zhou argued for a substantial role: “I think the tryptophan is actually a very integral part of this mechanism and I think not having the involvement of a tryptophan is too simplistic.” That is a statement of the proposed model, not proof that the exact pathway was settled.
The paper, “Insight into the Mechanism of the Influenza A Proton Channel from a Structure in a Lipid Bilayer,” paired its structural evidence with simulation to develop that mechanism. [Science, October 22, 2010]
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What differed between the experiments
| Feature | Iowa State study | Florida State study |
|---|---|---|
| Protein construct and system | Shorter M2 segment in a cholesterol-containing, virus-envelope-mimetic membrane. | Larger M2 construct with structural data from a lipid bilayer. |
| Main approach | Solid-state NMR focused on direct measurements of His37 structure and dynamics. | Bilayer structural data combined with simulations to develop a detailed transfer model. |
| Mechanistic emphasis | pH-dependent gating and dynamic proton shuttling by His37; ring-flip-assisted deprotonation was proposed as rate-limiting. | A proposed proton-transfer route involving water, His37, and Trp41. |
| Interpretive caution | The shorter construct and measured signals inform a model, but do not directly reveal each proton handoff. | The membrane system better resembles a viral membrane, while the particular bilayer experiments had lower resolution than some earlier detergent-based structural studies. |
These trade-offs were part of the contemporary discussion, not a general verdict on every membrane-protein method. Jason Schnell of the University of Oxford summarized the complementary appeal this way: “I like the construct that the Florida group used but I like the experiments that the Iowa group used.”
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What the findings did—and did not—establish
- Shared conclusion: His37 is central to M2’s pH-sensitive proton conduction.
- Open mechanistic question: The studies differed over the importance of Trp41, and the exact transfer route remained a proposed explanation supported by structural and dynamical evidence.
- Scope of the result: The experiments advanced basic understanding of a viral protein; they did not test whether changing M2 would produce an effective treatment in patients.
Mei Hong, whose group conducted the Iowa State study, framed the evidence question plainly: “I would say that the direct experimental result is more trustworthy.” In context, that reflects the distinction between experimental measurements and a more elaborate mechanistic interpretation, rather than a claim that simulations are inherently unhelpful.
How M2 research relates to older flu drugs
Amantadine and rimantadine are adamantane drugs that target the influenza A M2 channel. Resistance mutations have compromised their effectiveness against many influenza strains, so the 2010 structural findings should not be read as a recommendation to use them today. The cited structural studies do not establish current strain susceptibility or clinical guidance.
Earlier M2 research considered both pore-blocking and lipid-facing drug-binding models. A 2010 study in lipid bilayers reported a high-affinity pore site and a second, lower-affinity surface site at higher drug concentrations. These findings provide historical context for how researchers investigated drug binding; they do not demonstrate that either binding model offers a present-day treatment strategy. [Nature, February 4, 2010]
For background on M2 structure and mechanism, see Schnell and Chou’s 2008 review in Nature. [Nature, January 31, 2008] A separate 2010 review discussed resistance and the channel’s two drug-binding sites. [Protein & Cell, 2010]
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