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Publications (10 of 13) Show all publications
Lindahl, V., Gourdon, P., Andersson, M. & Hess, B. (2018). Permeability and ammonia selectivity in aquaporin TIP2;1: linking structure to function. Scientific Reports, 8, Article ID 2995.
Open this publication in new window or tab >>Permeability and ammonia selectivity in aquaporin TIP2;1: linking structure to function
2018 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 2995Article in journal (Refereed) Published
Abstract [en]

Aquaporin TIP2;1 is a protein channel permeable to both water and ammonia. The structural origin of ammonia selectivity remains obscure, but experiments have revealed that a double mutation renders it impermeable to ammonia without affecting water permeability. Here, we aim to reproduce and explain these observations by performing an extensive mutational study using microsecond long molecular dynamics simulations, applying the two popular force fields CHARMM36 and Amber ff99SB-ILDN. We calculate permeabilities and free energies along the channel axis for ammonia and water. For one force field, the permeability of the double mutant decreases by a factor of 2.5 for water and 4 for ammonia, increasing water selectivity by a factor of 1.6. We attribute this effect to decreased entropy of water in the pore, due to the observed increase in pore-water interactions and narrower pore. Additionally, we observe spontaneous opening and closing of the pore on the cytosolic side, which suggests a gating mechanism for the pore. Our results show that sampling methods and simulation times are sufficient to delineate even subtle effects of mutations on structure and function and to capture important long-timescale events, but also underline the importance of improving models further.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2018
National Category
Biological Sciences
Identifiers
urn:nbn:se:kth:diva-223791 (URN)10.1038/s41598-018-21357-2 (DOI)000424985800033 ()29445244 (PubMedID)2-s2.0-85042110483 (Scopus ID)
Funder
EU, European Research Council, 258980Swedish Research Council, 2014-4505Swedish e‐Science Research Center
Note

QC 20180307

Available from: 2018-03-07 Created: 2018-03-07 Last updated: 2018-03-07Bibliographically approved
Ravishankar, H., Barth, A. & Andersson, M. (2017). Probing the activity of a recombinant Zn2+-transporting P-type ATPase. Biopolymers
Open this publication in new window or tab >>Probing the activity of a recombinant Zn2+-transporting P-type ATPase
2017 (English)In: Biopolymers, ISSN 0006-3525, E-ISSN 1097-0282Article in journal (Refereed) [Artistic work] Published
National Category
Biophysics
Research subject
Biological Physics
Identifiers
urn:nbn:se:kth:diva-227201 (URN)10.1002/bip.23087 (DOI)000428629000003 ()2-s2.0-85035108666 (Scopus ID)
Note

QC 20180515

Available from: 2018-05-04 Created: 2018-05-04 Last updated: 2018-05-30Bibliographically approved
Gronberg, C., Sitsel, O., Lindahl, E., Gourdon, P. & Andersson, M. (2016). Membrane Anchoring and Ion-Entry Dynamics in P-type ATPase Copper Transport. Biophysical Journal, 111(11), 2417-2429
Open this publication in new window or tab >>Membrane Anchoring and Ion-Entry Dynamics in P-type ATPase Copper Transport
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2016 (English)In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 111, no 11, p. 2417-2429Article in journal (Refereed) Published
Abstract [en]

Cu+-specific P-type ATPase membrane protein transporters regulate cellular copper levels. The lack of crystal structures in Cu+-binding states has limited our understanding of how ion entry and binding are achieved. Here, we characterize the molecular basis of Cu+ entry using molecular-dynamics simulations, structural modeling, and in vitro and in vivo functional assays. Protein structural rearrangements resulting in the exposure of positive charges to bulk solvent rather than to lipid phosphates indicate a direct molecular role of the putative docking platform in Cu+ delivery. Mutational analyses and simulations in the presence and absence of Cu+ predict that the ion-entry path involves two ion-binding sites: one transient Met148-Cys382 site and one intramembranous site formed by trigonal coordination to Cys384, Asn689, and Met717. The results reconcile earlier biochemical and x-ray absorption data and provide a molecular understanding of ion entry in Cu+-transporting P-type ATPases.

Place, publisher, year, edition, pages
Elsevier, 2016
National Category
Biophysics Biophysics
Identifiers
urn:nbn:se:kth:diva-199485 (URN)10.1016/j.bpj.2016.10.020 (DOI)000389563900011 ()2-s2.0-85002251320 (Scopus ID)
Note

QC 20170120

Available from: 2017-01-20 Created: 2017-01-09 Last updated: 2018-01-11Bibliographically approved
Nys, M., Farinha, A., Wijckmans, E., Brams, M., Yoluk, Ö., Andersson, M., . . . Ulens, C. (2016). The Crystal Structure of ELIC in Complex with Chlorpromazine Unexpectedly Unveils an Allosteric Binding Site in the Ligand-Binding Domain. Paper presented at 60th Annual Meeting of the Biophysical-Society, FEB 27-MAR 02, 2016, Los Angeles, CA. Biophysical Journal, 110(3), 457A-457A
Open this publication in new window or tab >>The Crystal Structure of ELIC in Complex with Chlorpromazine Unexpectedly Unveils an Allosteric Binding Site in the Ligand-Binding Domain
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2016 (English)In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 110, no 3, p. 457A-457AArticle in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Cell Press, 2016
National Category
Biophysics
Identifiers
urn:nbn:se:kth:diva-187848 (URN)000375142700221 ()
Conference
60th Annual Meeting of the Biophysical-Society, FEB 27-MAR 02, 2016, Los Angeles, CA
Note

QC 20160530

Available from: 2016-05-30 Created: 2016-05-30 Last updated: 2017-11-30Bibliographically approved
Yazdi, S., Stein, M., Elinder, F., Andersson, M. & Lindahl, E. (2016). The Molecular Basis of Polyunsaturated Fatty Acid Interactions with the Shaker Voltage-Gated Potassium Channel. PloS Computational Biology, 12(1), Article ID e1004704.
Open this publication in new window or tab >>The Molecular Basis of Polyunsaturated Fatty Acid Interactions with the Shaker Voltage-Gated Potassium Channel
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2016 (English)In: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 12, no 1, article id e1004704Article in journal (Refereed) Published
Abstract [en]

Voltage-gated potassium (K-V) channels are membrane proteins that respond to changes in membrane potential by enabling K+ ion flux across the membrane. Polyunsaturated fatty acids (PUFAs) induce channel opening by modulating the voltage-sensitivity, which can provide effective treatment against refractory epilepsy by means of a ketogenic diet. While PUFAs have been reported to influence the gating mechanism by electrostatic interactions to the voltage-sensor domain (VSD), the exact PUFA-protein interactions are still elusive. In this study, we report on the interactions between the Shaker K-V channel in open and closed states and a PUFA-enriched lipid bilayer using microsecond molecular dynamics simulations. We determined a putative PUFA binding site in the open state of the channel located at the protein-lipid interface in the vicinity of the extracellular halves of the S3 and S4 helices of the VSD. In particular, the lipophilic PUFA tail covered a wide range of non-specific hydrophobic interactions in the hydrophobic central core of the protein-lipid interface, while the carboxylic head group displayed more specific interactions to polar/charged residues at the extracellular regions of the S3 and S4 helices, encompassing the S3-S4 linker. Moreover, by studying the interactions between saturated fatty acids (SFA) and the Shaker K-V channel, our study confirmed an increased conformational flexibility in the polyunsaturated carbon tails compared to saturated carbon chains, which may explain the specificity of PUFA action on channel proteins.

Place, publisher, year, edition, pages
PLOS, 2016
National Category
Bioinformatics (Computational Biology)
Identifiers
urn:nbn:se:kth:diva-183220 (URN)10.1371/journal.pcbi.1004704 (DOI)000369366100033 ()2-s2.0-84956717094 (Scopus ID)
Note

QC 20160303

Available from: 2016-03-03 Created: 2016-03-03 Last updated: 2018-01-10Bibliographically approved
Hariharan, P., Andersson, M., Jiang, X., Pardon, E., Steyaert, J., Kaback, H. R. & Guan, L. (2016). Thermodynamics of Nanobody Binding to Lactose Permease. Biochemistry, 55(42), 5917-5926
Open this publication in new window or tab >>Thermodynamics of Nanobody Binding to Lactose Permease
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2016 (English)In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 55, no 42, p. 5917-5926Article in journal (Refereed) Published
Abstract [en]

Camelid nanobodies (Nbs) raised against the outward-facing conformer of a double-Trp mutant of the lactose permease of Escherichia coli (LacY) stabilize the permease in outward-facing conformations. Isothermal titration calorimetry is applied herein to dissect the binding thermodynamics of two Nbs, one that markedly improves access to the sugar-binding site and another that dramatically increases the affinity for galactoside. The findings presented here show that both enthalpy and entropy contribute favorably to binding of the Nbs to wild-type (WT) LacY and that binding of Nb to double-Trp mutant G46W/G262W is driven by a greater enthalpy at an entropic penalty. Thermodynamic analyses support the interpretation that WT LacY is stabilized in outward-facing conformations like the double-Trp mutant with closure of the cytoplasmic cavity through conformational selection. The LacY conformational transition required for ligand binding is reflected by a favorable entropy increase. Molecular dynamics simulations further suggest that the entropy increase likely stems from release of immobilized water molecules primarily from the cytoplasmic cavity upon closure.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2016
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:kth:diva-196984 (URN)10.1021/acs.biochem.6b00826 (DOI)000386422100004 ()2-s2.0-84994031905 (Scopus ID)
Note

QC 20161213

Available from: 2016-12-13 Created: 2016-11-28 Last updated: 2017-11-29Bibliographically approved
Yoluk, O., Heusser, S., Andersson, M., Orellana, L. & Lindahl, E. (2015). Gating Ritual: Simulations of Gating in Glutamate-Gated Chloride Channel. Paper presented at 59th Annual Meeting of the Biophysical-Society, FEB 07-11, 2015, Baltimore, MD. Biophysical Journal, 108(2), 431A-431A
Open this publication in new window or tab >>Gating Ritual: Simulations of Gating in Glutamate-Gated Chloride Channel
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2015 (English)In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 108, no 2, p. 431A-431AArticle in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
CELL PRESS, 2015
National Category
Biophysics
Identifiers
urn:nbn:se:kth:diva-243704 (URN)000362849400581 ()
Conference
59th Annual Meeting of the Biophysical-Society, FEB 07-11, 2015, Baltimore, MD
Note

QC 20180227

Available from: 2019-02-27 Created: 2019-02-27 Last updated: 2019-05-22Bibliographically approved
Kimanius, D., Pettersson, I., Schluckebier, G., Lindahl, E. & Andersson, M. (2015). SAXS-Guided Metadynamics. Journal of Chemical Theory and Computation, 11(7), 3491-3498
Open this publication in new window or tab >>SAXS-Guided Metadynamics
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2015 (English)In: Journal of Chemical Theory and Computation, ISSN 1549-9618, E-ISSN 1549-9626, Vol. 11, no 7, p. 3491-3498Article in journal (Refereed) Published
Abstract [en]

The small-angle X-ray scattering (SAXS) methodology enables structural characterization of biological macromolecules in solution. However, because SAXS provides low-dimensional information, several potential structural configurations can reproduce the experimental scattering profile, which severely complicates the structural refinement process. Here, we present a bias-exchange metadynamics refinement protocol that incorporates SAXS data as collective variables and therefore tags all possible configurations with their corresponding free energies, which allows identification of a unique structural solution. The method has been implemented in PLUMED and combined with the GROMACS simulation package, and as a proof of principle, we explore the Trp-cage protein folding landscape.

National Category
Chemical Sciences Physical Sciences
Identifiers
urn:nbn:se:kth:diva-172178 (URN)10.1021/acs.jctc.5b00299 (DOI)000358104800057 ()2-s2.0-84949671194 (Scopus ID)
Note

QC 20150817

Available from: 2015-08-17 Created: 2015-08-14 Last updated: 2018-01-11Bibliographically approved
Yoluk, Ö., Riederer, E. A., Andersson, M., Klement, G., Trudell, J. R., Bertaccini, E. J., . . . Lindahl, E. (2014). Contribution of Structural Elements to Activation and Allosteric Modulation in an Anionic Ligand-Gated Ion Channel. Paper presented at 58th Annual Meeting of the Biophysical-Society, FEB 15-19, 2014, San Francisco, CA. Biophysical Journal, 106(2), 547A-547A
Open this publication in new window or tab >>Contribution of Structural Elements to Activation and Allosteric Modulation in an Anionic Ligand-Gated Ion Channel
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2014 (English)In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 106, no 2, p. 547A-547AArticle in journal, Meeting abstract (Other academic) Published
National Category
Biophysics
Identifiers
urn:nbn:se:kth:diva-147973 (URN)000337000403111 ()
Conference
58th Annual Meeting of the Biophysical-Society, FEB 15-19, 2014, San Francisco, CA
Note

QC 20140710

Available from: 2014-07-10 Created: 2014-07-10 Last updated: 2017-11-17Bibliographically approved
Jiang, X., Villafuerte, M. K., Andersson, M., White, S. H. & Kaback, H. R. (2014). Galactoside-binding site in LacY. Biochemistry, 53(9), 1536-1543
Open this publication in new window or tab >>Galactoside-binding site in LacY
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2014 (English)In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 53, no 9, p. 1536-1543Article in journal (Refereed) Published
Abstract [en]

Although an X-ray crystal structure of lactose permease (LacY) has been presented with bound galactopyranoside, neither the sugar nor the residues ligating the sugar can be identified with precision at ∼3.5 Å. Therefore, additional evidence is important for identifying side chains likely to be involved in binding. On the basis of a clue from site-directed alkylation suggesting that Asn272, Gly268, and Val264 on one face of helix VIII might participate in galactoside binding, molecular dynamics simulations were conducted initially. The simulations indicate that Asn272 (helix VIII) is sufficiently close to the galactopyranosyl ring of a docked lactose analogue to play an important role in binding, the backbone at Gly268 may be involved, and Val264 does not interact with the bound sugar. When the three side chains are subjected to site-directed mutagenesis, with the sole exception of mutant Asn272 → Gln, various other replacements for Asn272 either markedly decrease affinity for the substrate (i.e., high KD) or abolish binding altogether. However, mutant Gly268 → Ala exhibits a moderate 8-fold decrease in affinity, and binding by mutant Val264 → Ala is affected only minimally. Thus, Asn272 and possibly Gly268 may comprise additional components of the galactoside-binding site in LacY.

Keywords
Galactopyranoside, High- k, Lactose permease, Molecular dynamics simulations, Side-chains, Site directed mutagenesis, X ray crystal structures
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:kth:diva-161775 (URN)10.1021/bi401716z (DOI)000332913600016 ()24520888 (PubMedID)2-s2.0-84896088314 (Scopus ID)
Funder
EU, FP7, Seventh Framework Programme, FP7-MC-CIG-618558
Note

QC 20150401

Available from: 2015-04-01 Created: 2015-03-17 Last updated: 2017-12-04Bibliographically approved
Projects
Visualizing active membrane transport in real-time [2016-03610_VR]; Umeå University
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-3364-6647

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