7
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

      Ion-triggered selectivity in bacterial sodium channels

      research-article

      Read this article at

      ScienceOpenPublisherPMC
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Significance

          Voltage-gated Na + channels are essential components of the cell membrane in any realm of life. To perform their biological functions, Na + channels need to conduct Na + at high rates, while blocking K +. Molecular dynamics simulations showed that the selectivity filter of bacterial Na + channels is a highly flexible structure. This feature favors fast Na + conduction. However, it is still unknown how such highly flexible structure is able to select Na + over K +. In this contribution, we show that in the presence of K +, the selectivity filter switches to a nonconductive state. The effect of K + on the dynamics of Na + channels explains how these proteins can be contemporarily highly permeable to some ion species and highly selective for similar ones.

          Abstract

          Since the availability of the first crystal structure of a bacterial Na + channel in 2011, understanding selectivity across this family of membrane proteins has been the subject of intense research efforts. Initially, free energy calculations based on molecular dynamics simulations revealed that although sodium ions can easily permeate the channel with their first hydration shell almost intact, the selectivity filter is too narrow for efficient conduction of hydrated potassium ions. This steric view of selectivity was subsequently questioned by microsecond atomic trajectories, which proved that the selectivity filter appears to the permeating ions as a highly degenerate, liquid-like environment. Although this liquid-like environment looks optimal for rapid conduction of Na +, it seems incompatible with efficient discrimination between similar ion species, such as Na + and K +, through steric effects. Here extensive molecular dynamics simulations, combined with Markov state model analyses, reveal that at positive membrane potentials, potassium ions trigger a conformational change of the selectivity toward a nonconductive metastable state. It is this transition of the selectivity filter, and not steric effects, that prevents the outward flux of K + at positive membrane potentials. This description of selectivity, triggered by the nature of the permeating ions, might have implications on the current understanding of how ion channels, and in particular bacterial Na + channels, operate at the atomic scale.

          Related collections

          Most cited references30

          • Record: found
          • Abstract: found
          • Article: not found

          Improved treatment of the protein backbone in empirical force fields.

          Empirical force field-based calculations of proteins, including protein-folding studies, have improved our understanding of the relationship of their structure to their biological function. However, limitations in the accuracy of empirical force fields in the treatment of the peptide backbone exist. Presented is a grid correction approach to improve the treatment of the peptide backbone phi/psi conformational energies. Inclusion of this correction with the CHARMM22 all-atom protein force field is shown to lead to significant improvement in the treatment of the conformational energies of both the peptide model compound, the alanine dipeptide, and of proteins in their crystal environment. The developed approach is suggested to lead to significant improvements in the accuracy of empirical force fields to treat peptides and proteins.
            Bookmark
            • Record: found
            • Abstract: not found
            • Article: not found

            Finite representation of an infinite bulk system: Solvent boundary potential for computer simulations

              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Crystal structure of an orthologue of the NaChBac voltage-gated sodium channel.

              Voltage-gated sodium (Na(v)) channels are essential for the rapid depolarization of nerve and muscle, and are important drug targets. Determination of the structures of Na(v) channels will shed light on ion channel mechanisms and facilitate potential clinical applications. A family of bacterial Na(v) channels, exemplified by the Na(+)-selective channel of bacteria (NaChBac), provides a useful model system for structure-function analysis. Here we report the crystal structure of Na(v)Rh, a NaChBac orthologue from the marine alphaproteobacterium HIMB114 (Rickettsiales sp. HIMB114; denoted Rh), at 3.05 Å resolution. The channel comprises an asymmetric tetramer. The carbonyl oxygen atoms of Thr 178 and Leu 179 constitute an inner site within the selectivity filter where a hydrated Ca(2+) resides in the crystal structure. The outer mouth of the Na(+) selectivity filter, defined by Ser 181 and Glu 183, is closed, as is the activation gate at the intracellular side of the pore. The voltage sensors adopt a depolarized conformation in which all the gating charges are exposed to the extracellular environment. We propose that Na(v)Rh is in an 'inactivated' conformation. Comparison of Na(v)Rh with Na(v)Ab reveals considerable conformational rearrangements that may underlie the electromechanical coupling mechanism of voltage-gated channels.
                Bookmark

                Author and article information

                Journal
                Proc Natl Acad Sci U S A
                Proc. Natl. Acad. Sci. U.S.A
                pnas
                pnas
                PNAS
                Proceedings of the National Academy of Sciences of the United States of America
                National Academy of Sciences
                0027-8424
                1091-6490
                22 May 2018
                7 May 2018
                : 115
                : 21
                : 5450-5455
                Affiliations
                [1] aDepartment of Medical Biotechnologies, University of Siena , 53100 Siena, Italy;
                [2] bDepartment of Chemistry, University of Bath , Claverton Down, BA2 7AY Bath, United Kingdom;
                [3] cChemistry Research Laboratory, University of Oxford , OX1 3TA Oxford, United Kingdom
                Author notes
                1To whom correspondence should be addressed. Email: simone.furini@ 123456unisi.it .

                Edited by Michael L. Klein, Temple University, Philadelphia, PA, and approved April 16, 2018 (received for review January 9, 2018)

                Author contributions: S.F. and C.D. designed research; S.F. performed research; S.F. analyzed data; and S.F. and C.D. wrote the paper.

                Author information
                http://orcid.org/0000-0002-1099-8279
                Article
                PMC6003493 PMC6003493 6003493 201722516
                10.1073/pnas.1722516115
                6003493
                29735669
                f305884e-42dc-4cc4-8280-f0dbb593bf30
                Copyright @ 2018

                Published under the PNAS license.

                History
                Page count
                Pages: 6
                Categories
                Biological Sciences
                Biophysics and Computational Biology

                ion channels,membrane proteins,conduction,Markov state models,molecular dynamics

                Comments

                Comment on this article