Department of

Computational Biological Chemistry


grant holderChristian Schröder / T. Rungrotmongkol
funding period10/2023 - 09/2024


Influenza is a highly contagious respiratory disease that causes seasonal epidemics and occasional pandemics. The M2 protein of the influenza A virus is a membrane protein that plays a crucial role in the virus's replication cycle by mediating proton transport across the viral membrane. The M2 channel is a homotetramer consisting of four identical monomers that each contain a single transmembrane helix. The helices are arranged in a bundle that forms the channel's pore, which is lined with water molecules and contains two functionally important histidine residues (His37). The M2 channel undergoes conformational changes in response to the pH difference between the interior and exterior of the virus, which controls the flow of protons through the channel. Understanding the molecular mechanisms of proton transport through the M2 channel is, therefore, essential for developing effective therapies to combat influenza.

The main objective of this project is to use molecular dynamics (MD) simulations to investigate the molecular mechanisms of proton transport through the M2 channel in influenza viruses. Specifically, we aim to:
  • Determine the effects of the protonation state and pH on the conformational dynamics of the M2 channel.
  • Identify the key residues and interactions involved in proton transport through the channel.
  • Based on our findings, evaluate the inhibitory effects of known M2 channel blockers and identify potential new inhibitors.

We will use polarizable MD simulations using OpenMM and the newest CHARMM force field, including explicit proton transfers, to study the conformational dynamics of the M2 channel and the transport of protons and water molecules through the channel. Direct proton exchange simulations have some advantages over constant pH simulations:
  • They can provide a more detailed picture of the mechanism of proton transfer, including identifying intermediate states and analyzing rate constants.
  • Direct simulations can be used to study proton transfer reactions in systems where pH replica exchange is not feasible, for example, when the system is too large or when the proton transfer is coupled to conformational changes.
  • Finally, direct simulations allow for the study of non-equilibrium proton transfer, which cannot be modeled using constant pH simulations. Our MD simulations can provide a detailed picture of the dynamics of the proton transfer processes, including the role of specific amino acid residues in the proton pathway, the mechanism of proton transfer, and the effect of the membrane environment on the process.

  • Publications

Imprint: (as stipulated by Austrian law, MedienG 2005): S. Boresch / C. Schröder,
Institut für Computergestützte Biologische Chemie, Währinger Strasse 17, 1090 Wien, Austria