CITE.bib

@article{Perez-Conesa2023.04.05.535698,
  author = {Sergio Perez-Conesa and Lucie Delemotte},
  title = {Free energy landscapes of KcsA inactivation},
  elocation-id = {2023.04.05.535698},
  year = {2023},
  doi = {10.1101/2023.04.05.535698},
  publisher = {Cold Spring Harbor Laboratory},
  abstract = {The bacterial ion channel KcsA has become a useful model of
              complex K+-ion channels thanks to its single pore domain structure
              whose sequence shares many similarities with eukaryotic channels.
              Like many physiologically-relevant ion channels, KcsA inactivates
              after prolonged exposure to stimuli (in this case, a lowered pH).
              The inactivation mechanism has been heavily investigated, using
              structural, functional and simulations methods, but the molecular
              basis underlying the energetics of the process remains actively
              debated. In this work, we use the {\textquoteleft}{\textquoteleft}
              string method with swarms of trajectories{\textquoteright}{
              \textquoteright} enhanced sampling technique to characterize the
              free energy landscape lining the KcsA inactivation process. After
              channel opening following a pH drop, KcsA presents metastable open
              states leading to an inactivated state. The final inactivation step
              consists of a constriction of the selectivty filter and entry of
              three water molecules into binding sites behind each selectivity
              filter subunit. Based our simulations, we propose a key role for
              residue L81 in opening a gateway for water molecules to enter their
              buried sites, rather than for Y82 which has previously been
              suggested to act as a lid. In addition, since we found the
              energetically favored inactivation mechanism to be dependent on the
              force field, our results also address the importance of parameter
              choice for this type of mechanism. In particular, inactivation
              involves passing through the fully-open state only when using the
              AMBER force field. In contrast, using CHARMM, selectivity filter
              constriction proceeds directly from the partially open state.
              Finally, our simulations suggest that removing the co-purifying
              lipids stabilizes the partially open states, rationalizing their
              importance for the proper inactivation of the channel.Competing
              Interest StatementThe authors have declared no competing interest.},
  URL = {https://www.biorxiv.org/content/early/2023/04/06/2023.04.05.535698},
  eprint = {
            https://www.biorxiv.org/content/early/2023/04/06/2023.04.05.535698.full.pdf
            },
  journal = {bioRxiv},
}