title: Exploring the Dynamics of the TWIK-1 Channel.
abstract: Potassium channels in the two-pore domain family (K2P) have various structural attributes that differ from those of other K(+) channels, including a dimeric assembly constituted of nonidentical domains and an expansive extracellular cap. Crystallization of the prototypical K2P channel, TWIK-1, finally revealed the structure of these characteristics in atomic detail, allowing computational studies to be undertaken. In this study, we performed molecular-dynamics simulations for a cumulative time of ∼1 μs to discern the mechanism of ion transport throughout TWIK-1. We observed the free passage of ions beneath the extracellular cap and identified multiple high-occupancy sites in close proximity to charged residues on the protein surface. Despite the overall topological similarity of the x-ray structure of the selectivity filter to other K(+) channels, the structure diverges significantly in molecular-dynamics simulations as a consequence of nonconserved residues in both pore domains contributing to the selectivity filter (T118 and L228). The behavior of such residues has been linked to channel inactivation and the phenomenon of dynamic selectivity, where TWIK-1 displays robust Na(+) inward flux in response to subphysiological K(+) concentrations.
authors: Department of Chemistry, King's College London, London, United Kingdom.
authors: Victoria
authors: V
authors: Oakes
authors: Department of Medical Biotechnologies, University of Siena, Siena, Italy.
authors: Simone
authors: S
authors: Furini
authors: Worldwide Medicinal Chemistry, Pfizer Neuroscience and Pain Research Unit, Cambridge, United Kingdom.
authors: David
authors: D
authors: Pryde
authors: Department of Chemistry, King's College London, London, United Kingdom; Chemistry Research Laboratory, Mansfield Road, University of Oxford, Oxford, United Kingdom. Electronic address: carmen.domene@kcl.ac.uk.
authors: Carmen
authors: C
authors: Domene
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D056004:Molecular Dynamics Simulation; D024683:Potassium Channels, Tandem Pore Domain / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation
chemical_list: C109137:KCNK1 protein, human; D024683:Potassium Channels, Tandem Pore Domain