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  • 1. Aman, K.
    et al.
    Lindahl, E.
    Edholm, Olle
    KTH, Superseded Departments, Physics.
    Hakansson, P.
    Westlund, P. O.
    Structure and dynamics of interfacial water in an L-alpha phase lipid bilayer from molecular dynamics simulations2003In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 84, no 1, p. 102-115Article in journal (Refereed)
    Abstract [en]

    Based on molecular dynamics simulations, an analysis of structure and dynamics is performed on interfacial water at a liquid crystalline dipalmitoylphosphatidycholine/water system. Water properties relevant for understanding NMR relaxation are emphasized. The first and second rank orientational order parameters of the water O-H bonds were calculated, where the second rank order parameter is in agreement with experimental determined quadrupolar splittings. Also, two different interfacial water regions (bound water regions) are revealed with respect to different signs of the second rank order parameter. The water reorientation correlation function reveals a mixture of fast and slow decaying parts. The fast (ps) part of the correlation function is due to local anisotropic water reorientation whereas the much slower part is due to more complicated processes including lateral diffusion along the interface and chemical exchange between free and bound water molecules. The 100-ns-long molecular dynamics simulation at constant pressure (1 atm) and at a temperature of 50degreesC of 64 lipid molecules and 64 x 23 water molecules lack a slow water reorientation correlation component in the ns time scale. The (H2O)-H-2 powder spectrum of the dipalmitoylphosphatidycholine/water system is narrow and consequently, the NMR relaxation time T-2 is too short compared to experimental results.

  • 2.
    Aman, Ken
    et al.
    Umeå University.
    Lindahl, Erik
    KTH, Superseded Departments, Physics.
    Edholm, Olle
    KTH, Superseded Departments, Physics.
    Håkansson, Pär
    Umeå University.
    Westlund, Per-Olof
    Umeå University.
    Structure and dynamics of interfacial water in an Lalpha phase lipid bilayer from molecular dynamics simulations.2003In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 84, no 1, p. 102-15Article in journal (Refereed)
    Abstract [en]

    Based on molecular dynamics simulations, an analysis of structure and dynamics is performed on interfacial water at a liquid crystalline dipalmitoylphosphatidycholine/water system. Water properties relevant for understanding NMR relaxation are emphasized. The first and second rank orientational order parameters of the water O-H bonds were calculated, where the second rank order parameter is in agreement with experimental determined quadrupolar splittings. Also, two different interfacial water regions (bound water regions) are revealed with respect to different signs of the second rank order parameter. The water reorientation correlation function reveals a mixture of fast and slow decaying parts. The fast (ps) part of the correlation function is due to local anisotropic water reorientation whereas the much slower part is due to more complicated processes including lateral diffusion along the interface and chemical exchange between free and bound water molecules. The 100-ns-long molecular dynamics simulation at constant pressure (1 atm) and at a temperature of 50 degrees C of 64 lipid molecules and 64 x 23 water molecules lack a slow water reorientation correlation component in the ns time scale. The (2)H(2)O powder spectrum of the dipalmitoylphosphatidycholine/water system is narrow and consequently, the NMR relaxation time T(2) is too short compared to experimental results.

  • 3.
    Andersson, Magnus
    et al.
    KTH, School of Engineering Sciences (SCI), Theoretical Physics.
    Lindahl, Erik
    Stockholm Univ, Dept Biochem & Biophys, S-10691 Stockholm, Sweden..
    White, Stephen H.
    Univ Calif Irvine, Irvine, CA USA..
    Kaback, Ronald H.
    Univ Calif Los Angeles, Los Angeles, CA USA..
    The Molecular Basis for Substrate Specificity in Lactose Permease2015In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 108, no 2, p. 309A-309AArticle in journal (Other academic)
  • 4.
    Andersson, Magnus
    et al.
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Mattle, Daniel
    Sitsel, Oleg
    Nielsen, Anna Marie
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Applied Physics, Experimental Biomolecular Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    White, Stephen H.
    Nissen, Poul
    Gourdon, Pontus
    Transport Pathway in Cu+ P-Type ATPases2014In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 106, no 2, p. 427A-427AArticle in journal (Other academic)
  • 5. Beckham, Gregg T.
    et al.
    Bomble, Yannick J.
    Matthews, James F.
    Taylor, Courtney B.
    Resch, Michael G.
    Yarbrough, John M.
    Decker, Steve R.
    Bu, Lintao
    Zhao, Xiongce
    McCabe, Clare
    Wohlert, Jakob
    Bergenstråhle, Malin
    KTH, School of Chemical Science and Engineering (CHE), Centres, Wallenberg Wood Science Center.
    Brady, John W.
    Adney, William S.
    Himmel, Michael E.
    Crowley, Michael F.
    The O-Glycosylated Linker from the Trichoderma reesei Family 7 Cellulase Is a Flexible, Disordered Protein2010In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 99, no 11, p. 3773-3781Article in journal (Refereed)
    Abstract [en]

    Fungi and bacteria secrete glycoprotein cocktails to deconstruct cellulose Cellulose degrading enzymes (cellulases) are often modular with catalytic domains for cellulose hydrolysis and carbohydrate binding modules connected by linkers rich in serine and threonine with O-glycosylation Few studies have probed the role that the linker and O-glycans play in catalysis Since different expression and growth conditions produce different glycosylation patterns that affect enzyme activity the structure function relationships that glycosylation imparts to linkers are relevant for understanding cellulase mechanisms Here the linker of the Trichoderma reesei Family 7 cellobiohydrolase (Cel7A) is examined by simulation Our results suggest that the Cel7A linker is an intrinsically disordered protein with and without glycosylation Contrary to the predominant view the O-glycosylation does not change the stiffness of the linker as measured by the relative fluctuations in the end to end distance rather it provides a 16 A extension thus expanding the operating range of Cel7A We explain observations from previous biochemical experiments in the light of results obtained here and compare the Cel7A linker with linkers from other cellulases with sequence based tools to predict disorder This preliminary screen indicates that linkers from Family 7 enzymes from other genera and other cellulases within T reesei may not be as disordered warranting further study

  • 6. Benninger, R. K. P.
    et al.
    Önfelt, Björn
    Neil, M. A. A.
    Davis, D. M.
    French, P. M. W.
    Fluorescence imaging of two-photon linear dichroism: Cholesterol depletion disrupts molecular orientation in cell membranes2005In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 88, no 1, p. 609-622Article in journal (Refereed)
    Abstract [en]

    The plasma membrane of cells is an ordered environment, giving rise to anisotropic orientation and restricted motion of molecules and proteins residing in the membrane. At the same time as being an organized matrix of defined structure, the cell membrane is heterogeneous and dynamic. Here we present a method where we use fluorescence imaging of linear dichroism to measure the orientation of molecules relative to the cell membrane. By detecting linear dichroism as well as fluorescence anisotropy, the orientation parameters are separated from dynamic properties such as rotational diffusion and homo energy transfer ( energy migration). The sensitivity of the technique is enhanced by using two-photon excitation for higher photo-selection compared to single photon excitation. We show here that we can accurately image lipid organization in whole cell membranes and in delicate structures such as membrane nanotubes connecting two cells. The speed of our wide-field imaging system makes it possible to image changes in orientation and anisotropy occurring on a subsecond timescale. This is demonstrated by time-lapse studies showing that cholesterol depletion rapidly disrupts the orientation of a fluorophore located within the hydrophobic region of the cell membrane but not of a surface bound probe. This is consistent with cholesterol having an important role in stabilizing and ordering the lipid tails within the plasma membrane.

  • 7. Benninger, Richard K. P.
    et al.
    Vanherberghen, Bruno
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Young, Stephen
    Taner, Sabrina B.
    Culley, Fiona I.
    Schnyder, Tim
    Neil, Mark A. A.
    Wuestner, Daniel
    French, Paul M. W.
    Davis, Daniel M.
    Önfelt, Björn
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Live Cell Linear Dichroism Imaging Reveals Extensive Membrane Ruffling within the Docking Structure of Natural Killer Cell Immune Synapses2009In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 96, no 2, p. L13-L15Article in journal (Refereed)
    Abstract [en]

    We have applied fluorescence imaging of two-photon linear dichroism to measure the subresolution organization of the cell membrane during formation of the activating (cytolytic) natural killer (NK) cell immune synapse (IS). This approach revealed that the NK cell plasma membrane is convoluted into ruffles at the periphery, but not in the center of a mature cytolytic NK cell IS. Time-lapse imaging showed that the membrane ruffles formed at the initial point of contact between NK cells and target cells and then spread radialy across the intercellular contact as the size of the IS increased, becoming absent from the center of the mature synapse. Understanding the role of such extensive membrane ruff ling in the assembly of cytolytic synapses is an intriguing new goal.

  • 8.
    Bergh, Cathrine
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics.
    Orellana, Laura
    Stockholm Univ, Dept Biochem & Biophys, Stockholm, Sweden..
    Howard, Rebecca J.
    Stockholm Univ, Dept Biochem & Biophys, Stockholm, Sweden..
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Applied Physics. Stockholm Univ, Dept Biochem & Biophys, Stockholm, Sweden..
    Understanding the Conformational Dynamics of a Pentameric Ligand-Gated Ion Channel through Markov State Modeling2019In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 116, no 3, p. 395A-396AArticle in journal (Other academic)
  • 9. Blau, Christian
    Gromaps: A Gromacs-Based Toolset to Analyse Density Maps Derived from Molecular Dynamics Simulations2019In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 116, no 1, p. 4-11Article in journal (Refereed)
    Abstract [en]

    We introduce a computational toolset, named GROmaρs, to obtain and compare time-averaged density maps from molecular dynamics simulations. GROmaρs efficiently computes density maps by fast multi-Gaussian spreading of atomic densities onto a three-dimensional grid. It complements existing map-based tools by enabling spatial inspection of atomic average localization during the simulations. Most importantly, it allows the comparison between computed and reference maps (e.g., experimental) through calculation of difference maps and local and time-resolved global correlation. These comparison operations proved useful to quantitatively contrast perturbed and control simulation data sets and to examine how much biomolecular systems resemble both synthetic and experimental density maps. This was especially advantageous for multimolecule systems in which standard comparisons like RMSDs are difficult to compute. In addition, GROmaρs incorporates absolute and relative spatial free-energy estimates to provide an energetic picture of atomistic localization. This is an open-source GROMACS-based toolset, thus allowing for static or dynamic selection of atoms or even coarse-grained beads for the density calculation. Furthermore, masking of regions was implemented to speed up calculations and to facilitate the comparison with experimental maps. Beyond map comparison, GROmaρs provides a straightforward method to detect solvent cavities and average charge distribution in biomolecular systems. We employed all these functionalities to inspect the localization of lipid and water molecules in aquaporin systems, the binding of cholesterol to the G protein coupled chemokine receptor type 4, and the identification of permeation pathways through the dermicidin antimicrobial channel. Based on these examples, we anticipate a high applicability of GROmaρs for the analysis of molecular dynamics simulations and their comparison with experimentally determined densities.

  • 10.
    Brandt, Erik G.
    et al.
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical Biological Physics.
    Braun, Anthony R.
    Sachs, Jonathan N.
    Nagle, John F.
    Edholm, Olle
    KTH, School of Engineering Sciences (SCI), Theoretical Physics.
    Interpretation of Fluctuation Spectra in Lipid Bilayer Simulations2011In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 100, no 9, p. 2104-2111Article in journal (Refereed)
    Abstract [en]

    Atomic resolution and coarse-grained simulations of dimyristoylphosphatidylcholine lipid bilayers were analyzed for fluctuations perpendicular to the bilayer using a completely Fourier-based method. We find that the fluctuation spectrum of motions perpendicular to the bilayer can be decomposed into just two parts: 1), a pure undulation spectrum proportional to q(-4) that dominates in the small-q regime; and 2), a molecular density structure factor contribution that dominates in the large-q regime. There is no need for a term proportional to q(-2) that has been postulated for protrusion fluctuations and that appeared to have been necessary to fit the spectrum for intermediate q. We suggest that earlier reports of such a term were due to the artifact of binning and smoothing in real space before obtaining the Fourier spectrum. The observability of an intermediate protrusion regime from the fluctuation spectrum is discussed based on measured and calculated material constants.

  • 11.
    Brandt, Erik G.
    et al.
    KTH, School of Engineering Sciences (SCI), Theoretical Physics.
    Edholm, Olle
    KTH, School of Engineering Sciences (SCI), Theoretical Physics.
    Dynamic structure factors from lipid membrane molecular dynamics simulations2009In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 96, no 5, p. 1828-1838Article in journal (Refereed)
    Abstract [en]

    Dynamic structure factors for a lipid bilayer have been calculated from molecular dynamics simulations. From trajectories of a system containing 1024 lipids we obtain wave vectors down to 0.34 nm(-1), which enables us to directly resolve the Rayleigh and Brillouin lines of the spectrum. The results confirm the validity of a model based on generalized hydrodynamics, but also improves the line widths and the position of the Brillouin lines. The improved resolution shows that the Rayleigh line is narrower than in earlier studies, which corresponds to a smaller thermal diffusivity. From a detailed analysis of the power spectrum, we can, in fact, distinguish two dispersive contributions to the elastic scattering. These translate to two exponential relaxation processes in separate time domains. Further, by including a first correction to the wave-vector-dependent position of the Brillouin lines, the results agree favorably to generalized hydrodynamics even up to intermediate wave vectors, and also yields a 20% higher adiabatic sound velocity. The width of the Brillouin lines shows a linear, not quadratic, dependence to low wave vectors.

  • 12.
    Brandt, Erik G.
    et al.
    KTH, School of Engineering Sciences (SCI), Theoretical Physics.
    Edholm, Olle
    KTH, School of Engineering Sciences (SCI), Theoretical Physics.
    Dynamic Structure Factors From Lipid Membrane Molecular Dynamics Simulations2009In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 96, no 3, p. 354A-354AArticle in journal (Other academic)
  • 13.
    Brandt, Erik G.
    et al.
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical Biological Physics.
    Edholm, Olle
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical Biological Physics.
    Molecular Dynamics Simulations of In-Plane Density Fluctuations in Phospholipid Bilayers2010In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 98, no 3, p. 664A-664AArticle in journal (Other academic)
  • 14. Braun, Anthony R.
    et al.
    Brandt, Erik G.
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical Biological Physics.
    Edholm, Olle
    KTH, School of Engineering Sciences (SCI), Theoretical Physics.
    Nagle, John F.
    Sachs, Jonathan N.
    Determination of Electron Density Profiles and Area from Simulations of Undulating Membranes2011In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 100, no 9, p. 2112-2120Article in journal (Refereed)
    Abstract [en]

    The traditional method for extracting electron density and other transmembrane profiles from molecular dynamics simulations of lipid bilayers fails for large bilayer systems, because it assumes a flat reference surface that does not take into account long wavelength undulations. We have developed what we believe to be a novel set of methods to characterize these undulations and extract the underlying profiles in the large systems. Our approach first obtains an undulation reference surface for each frame in the simulation and subsequently isolates the long-wavelength undulations by filtering out the intrinsic short wavelength modes. We then describe two methods to obtain the appropriate profiles from the undulating reference surface. Most combinations of methods give similar results for the electron density profiles of our simulations of 1024 DMPC lipids. From simulations of smaller systems, we also characterize the finite size effect related to the boundary conditions of the simulation box. In addition, we have developed a set of methods that use the undulation reference surface to determine the true area per lipid which, due to undulations, is larger than the projected area commonly reported from simulations.

  • 15. Conti, Luca
    et al.
    Renhorn, Jakob
    Gabrielsson, Anders
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Turesson, Fredrik
    Liin, Sara
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Elinder, Fredrik
    A Reciprocal Voltage Sensor-To-Pore Coupling in C-Type Inactivation2016In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 110, no 3, p. 104A-104AArticle in journal (Other academic)
  • 16.
    Delemotte, Lucie
    et al.
    KTH, School of Engineering Sciences (SCI), Physics, Theoretical & Computational Biophysics.
    van Keulen, Siri
    Roethlisberger, Ursula
    Gianti, Eleonora
    Carnevale, Vincenzo
    Klein, Michael L.
    Does Proton Conduction in the Voltage-Gated Proton Channel hH(V)1 Involve Grotthus Hopping via Acidic Residues?2017In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 112, no 3, p. 163A-164AArticle in journal (Other academic)
  • 17.
    Delemotte, Lucie
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Westerlund, Annie M.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Blau, Christian
    Stockholm Univ, Stockholm, Sweden..
    Robust Estimation of Free Energy Landscapes from Gaussian Mixture Models with Cross-Validation2019In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 116, no 3, p. 303A-303AArticle in journal (Other academic)
  • 18. Doerr, Denis
    et al.
    Sandrin, Deborah
    Kalinin, Stanislav
    Kuehnemuth, Ralf
    Overmann, Sebastian
    Pfiffi, Daniela
    Schaper, Klaus
    Seidel, Claus A. M.
    Mueller, Thomas J. J.
    Chmyrov, Andriy
    Widengren, Jerker
    KTH, School of Engineering Sciences (SCI), Applied Physics, Experimental Biomolecular Physics.
    Bier, Brigitte A.
    Maximizing the Fluorescence Signal and Photostability of Fluorophores by Quenching Dark-States2014In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 106, no 2, p. 196A-196AArticle in journal (Other academic)
  • 19. dos Remedios, Cristobal G.
    et al.
    Estigoy, Colleen
    Cameron, Darryl
    Ho, Joshua W. K.
    Herbert, Benjamin
    Padula, Matthew
    Pickford, Russel
    Guilhaus, Michael
    Odeberg, Jacob
    KTH, School of Biotechnology (BIO), Proteomics (closed 20130101).
    Ponten, Fredrik
    Proteomics of the Human Cardiac Intercalated Disc: A More Complex Multi-Functional Structure than was Previously Thought2010In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 98, no 3, p. 755A-756AArticle in journal (Other academic)
  • 20.
    Edholm, O
    KTH, Superseded Departments (pre-2005), Physics.
    Dynamics of lipid bilayers from molecular dynamics simulations2005In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 88, no 1, p. 26A-26AArticle in journal (Other academic)
  • 21.
    Edholm, O
    KTH, Superseded Departments (pre-2005), Physics.
    Simulations of lipid bilayers on mesoscopic scales: Issues, answers and challenges.2005In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 88, no 1, p. 32A-32AArticle in journal (Other academic)
  • 22.
    Edholm, Olle
    et al.
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical Biological Physics.
    Nagle, J. F.
    Areas of molecules in membranes consisting of mixtures2005In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 89, no 3, p. 1827-1832Article in journal (Refereed)
    Abstract [en]

    The question has arisen in recent literature: how to partition the total area in simulations of membranes consisting of more than one kind of molecule into average areas for each kind of molecule. Several definitions have been proposed, each of which has arbitrary features. When applied to mixtures of cholesterol and DPPC, these definitions give different results. This note recalls that physical chemistry provides a canonical way to de. ne molecular area, in analogy to the definition of partial-specific volume. Results for partial-specific area are obtained from simulations of DPPC/cholesterol bilayers and compared to the results from the other recent definitions. The partial-specific-area formalism dramatically demonstrates the condensing effect of cholesterol and this leads to the introduction of a specific model that accounts for the area of mixtures of cholesterol and lipid over the entire range of cholesterol concentrations.

  • 23.
    Edholm, Olle
    et al.
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical Biological Physics.
    Tjörnhammar, Richard
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical Biological Physics.
    Waheed, Qaiser
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical Biological Physics.
    Cholesterol/Phospholipid Bilayer Phase Diagrams from Coarse Grained Simulations2013In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 104, no 2, p. 590A-590AArticle in journal (Other academic)
  • 24.
    Farsi, Zohreh
    et al.
    Helmholtz Assoc, Max Delbruck Ctr Mol Med, Light Microscopy Platform, Berlin, Germany..
    Gowrisankaran, Sindhuja
    European Neurosci Inst, Gottingen, Germany..
    Krunic, Matija
    European Neurosci Inst, Gottingen, Germany..
    Rammner, Burkhard
    Sciloop, Hamburg, Germany..
    Woehler, Andrew
    Helmholtz Assoc, Max Delbruck Ctr Mol Med, Light Microscopy Platform, Berlin, Germany..
    Mim, Carsten
    KTH, School of Technology and Health (STH).
    Jahn, Reinhard
    Max Planck Inst Biophys Chem, Neurobiol, Gottingen, Germany..
    Milosevic, Ira
    European Neurosci Inst, Synapt Vesicle Dynam, Gottingen, Germany..
    Clathrin Coat Controls Vesicle Acidification by Blocking Vacuolar ATPase Activity2018In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 114, no 3, p. 280A-280AArticle in journal (Other academic)
  • 25.
    Fleetwood, Oliver
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Kasimova, Marina A.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Westerlund, Annie M.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Delemotte, Lucie
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Molecular Insights from Conformational Ensembles via Machine Learning2020In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 118, no 3, p. 765-780Article in journal (Refereed)
    Abstract [en]

    Biomolecular simulations are intrinsically high dimensional and generate noisy data sets of ever-increasing size. Extracting important features from the data is crucial for understanding the biophysical properties of molecular processes, but remains a big challenge. Machine learning (ML) provides powerful dimensionality reduction tools. However, such methods are often criticized as resembling black boxes with limited human-interpretable insight. We use methods from supervised and unsupervised ML to efficiently create interpretable maps of important features from molecular simulations. We benchmark the performance of several methods, including neural networks, random forests, and principal component analysis, using a toy model with properties reminiscent of macromolecular behavior. We then analyze three diverse biological processes: conformational changes within the soluble protein calmodulin, ligand binding to a G protein-coupled receptor, and activation of an ion channel voltage-sensor domain, unraveling features critical for signal transduction, ligand binding, and voltage sensing. This work demonstrates the usefulness of ML in understanding biomolecular states and demystifying complex simulations.

  • 26. Fridberger, A.
    et al.
    Widengren, Jerker
    KTH, School of Engineering Sciences (SCI), Applied Physics, Experimental Biomolecular Physics.
    de Monvel, J. B.
    Measuring hearing organ vibration patterns with confocal microscopy and optical flow2004In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 86, no 1, p. 535-543Article in journal (Refereed)
    Abstract [en]

    A new method for visualizing vibrating structures is described. The system provides a means to capture very fast repeating events by relatively minor modi. cations to a standard confocal microscope. An acousto-optic modulator was inserted in the beam path, generating brief pulses of laser light. Images were formed by summing consecutive frames until every pixel of the resulting image had been exposed to a laser pulse. Images were analyzed using a new method for optical flow computation; it was validated through introducing artificial displacements in confocal images. Displacements in the range of 0.8 to 4 pixels were measured with 5% error or better. The lower limit for reliable motion detection was 20% of the pixel size. These methods were used for investigating the motion pattern of the vibrating hearing organ. In contrast to standard theory, we show that the organ of Corti possesses several degrees of freedom during sound-evoked vibration. Outer hair cells showed motion indicative of deformation. After acoustic overstimulation, supporting cells contracted. This slowly developing structural change was visualized during simultaneous intense sound stimulation and its speed measured with the optical flow technique.

  • 27. Gabba, M.
    et al.
    Frallicciardi, J.
    van ’t Klooster, J.
    Henderson, R.
    Syga, Ł.
    Mans, R.
    van Maris, Antonius J. A.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Industrial Biotechnology.
    Poolman, B.
    Weak Acid Permeation in Synthetic Lipid Vesicles and Across the Yeast Plasma Membrane2020In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 118, no 2, p. 422-434Article in journal (Refereed)
    Abstract [en]

    We present a fluorescence-based approach for determination of the permeability of small molecules across the membranes of lipid vesicles and living cells. With properly designed experiments, the method allows us to assess the membrane physical properties both in vitro and in vivo. We find that the permeability of weak acids increases in the order of benzoic > acetic > formic > lactic, both in synthetic lipid vesicles and the plasma membrane of Saccharomyces cerevisiae, but the permeability is much lower in yeast (one to two orders of magnitude). We observe a relation between the molecule permeability and the saturation of the lipid acyl chain (i.e., lipid packing) in the synthetic lipid vesicles. By analyzing wild-type yeast and a manifold knockout strain lacking all putative lactic acid transporters, we conclude that the yeast plasma membrane is impermeable to lactic acid on timescales up to ∼2.5 h.

  • 28.
    Gabrielsson, Anders
    et al.
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Liin, Sara
    Elinder, Fredrik
    Lindahl, Erik
    Binding Structure & Dynamics for Toxins Modifying the Gating Mechanism of Kv Channels2014In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 106, no 2, p. 738A-738AArticle in journal (Other academic)
  • 29. Geissbuehler, Matthias
    et al.
    Spielmann, Thiemo
    KTH, School of Engineering Sciences (SCI), Applied Physics, Experimental Biomolecular Physics.
    Formey, Aurlie
    Maerki, Iwan
    Leutenegger, Marcel
    Hinz, Boris
    Johnsson, Kai
    Van De Ville, Dimitri
    Lasser, Theo
    Triplet Imaging of Oxygen Consumption during the Contraction of a Single Smooth Muscle Cell (A7r5)2010In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 98, no 2, p. 339-349Article in journal (Refereed)
    Abstract [en]

    The measurement of tissue and cell oxygenation is important for understanding cell metabolism. We have addressed this problem with a novel optical technique, called triplet imaging, that exploits oxygen-induced triplet lifetime changes and is compatible with a variety of fluorophores. A modulated excitation of varying pulse widths allows the extraction of the lifetime of the essentially dark triplet state using a high-fluorescence signal intensity. This enables the monitoring of fast kinetics of oxygen concentration in living cells combined with high temporal and spatial resolution. First, the oxygen-dependent triplet-state quenching of tetramethylrhodamine is validated and then calibrated in an L-ascorbic acid titration experiment demonstrating the linear relation between triplet lifetime and oxygen concentration according to the Stern-Volmer equation. Second, the method is applied to a biological cell system, employing as reporter a cytosolic fusion protein of beta-galactosidase with SNAP-tag labeled with tetramethylrhodamine. Oxygen consumption in single smooth muscle cells A7r5 during an [Arg(8)]-vasopressin-induced contraction is measured. The results indicate a consumption leading to an intracellular oxygen concentration that decays monoexponentially with time. The proposed method has the potential to become a new tool for investigating oxygen metabolism at the single cell and the subcellular level.

  • 30. Gronberg, Christina
    et al.
    Sitsel, Oleg
    Lindahl, Erik
    Gourdon, Pontus
    Andersson, Magnus
    KTH, School of Engineering Sciences (SCI), Theoretical Physics. KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Membrane Anchoring and Ion-Entry Dynamics in P-type ATPase Copper Transport2016In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 111, no 11, p. 2417-2429Article in journal (Refereed)
    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.

  • 31.
    Heinz, William F.
    et al.
    Johns Hopkins Sch Med, Physiol, Baltimore, MD USA.;Helianthus LLC, Sykesville, MD USA..
    Werbin, Jeffrey
    Johns Hopkins Sch Med, Physiol, Baltimore, MD USA.;RareCyte Inc, Seattle, WA USA..
    Hoh, Jan H
    KTH.
    Restricted Exchange Environment Chambers for Creating and Manipulating Diffusive Gradients in 2D Cell Culture2015In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 108, no 2, p. 458A-458AArticle in journal (Other academic)
  • 32.
    Hermanowska, Malgorzata
    et al.
    Univ Southern Denmark, Dept Phys & Chem, Odense M, Denmark.;Univ Southern Denmark, MEMPHYS, Odense M, Denmark..
    Bijelic, Goran
    KTH, School of Chemical Science and Engineering (CHE).
    Ciobanasu, Corina
    Univ Bonn, Inst Phys & Theoret Chem, Bonn, Germany..
    Kubitscheck, Ulrich
    Univ Bonn, Inst Phys & Theoret Chem, Bonn, Germany..
    Claesson, Per M.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Chemistry, Surface and Corrosion Science.
    Klosgen, Beate M.
    Univ Southern Denmark, Dept Phys & Chem, Odense M, Denmark.;Univ Southern Denmark, MEMPHYS, Odense M, Denmark..
    Charges in phospholipid layers2009In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 96, no 3, p. 18A-18AArticle in journal (Other academic)
  • 33. Heusser, Stephanie A.
    et al.
    Howard, Rebecca J.
    Pouya, Iman
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Klement, Göran
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Borghese, Cecilia
    Harris, R. Adron
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab. Stockholms universitet.
    A Single Mutation in GLIC Reveals Both the Potentiating and the Inhibitory Nature of Propofol2016In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 110, no 3, p. 456A-456AArticle in journal (Other academic)
  • 34.
    Heusser, Stephanie A.
    et al.
    Stockholm Univ, Dept Biochem & Biophys, SciLifeLab, Stockholm, Sweden..
    Lycksell, Marie
    Stockholm Univ, Dept Biochem & Biophys, SciLifeLab, Stockholm, Sweden..
    Wang, Xueqing
    KTH, School of Engineering Sciences (SCI), Theoretical Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab. Stockholm Univ, Dept Biochem & Biophys, SciLifeLab, Stockholm, Sweden.
    Howard, Rebecca J.
    Stockholm Univ, Dept Biochem & Biophys, SciLifeLab, Stockholm, Sweden..
    Lindahl, Erik
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences (SCI), Theoretical Physics. Stockholm Univ, Dept Biochem & Biophys, SciLifeLab, Stockholm, Sweden.
    Flexibility of a Transmembrane Helix Underlies Dramatic Reversal of Net Anesthetic Effects in a Pentameric Ligand-Gated Ion Channel2018In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 114, no 3, p. 488A-489AArticle in journal (Other academic)
  • 35.
    Heusser, Stephanie A.
    et al.
    SciLifeLab, Solna, Sweden.;Stockholm Univ, S-10691 Stockholm, Sweden..
    Yoluk, Ozge
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Lindahl, Erik
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Exploring the Gating Pathway in an Eukaryotic Ligand-Gated Ion Channel2015In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 108, no 2, p. 433A-433AArticle in journal (Other academic)
  • 36. Hofsass, C.
    et al.
    Lindahl, E.
    Edholm, Olle
    KTH, Superseded Departments, Physics.
    Molecular dynamics simulations of phospholipid bilayers with cholesterol2003In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 84, no 4, p. 2192-2206Article in journal (Refereed)
    Abstract [en]

    To investigate the microscopic interactions between cholesterol and lipids in biological membranes, we have performed a series of molecular dynamics simulations of large membranes with different levels of cholesterol content. The simulations extend to 10 ns, and were performed with hydrated dipalmitoylphosphatidylcholine (DPPC) bilayers. The bilayers contain 1024 lipids of which 0-40% were cholesterol and the rest DPPC. The effects of cholesterol on the structure and mesoscopic dynamics of the bilayer were monitored as a function of cholesterol concentration. The main effects observed are a significant ordering of the DPPC chains (as monitored by NMR type order parameters), a reduced fraction of gauche bonds, a reduced surface area per lipid, less undulations-corresponding to an increased bending modulus for the membrane, smaller area fluctuations, and a reduced lateral diffusion of DPPC-lipids as well as cholesterols.

  • 37.
    Hofsäss, Christofer
    et al.
    KTH, Superseded Departments, Physics.
    Lindahl, Erik
    KTH, Superseded Departments, Physics.
    Edholm, Olle
    KTH, Superseded Departments, Physics.
    Molecular dynamics simulations of phospholipid bilayers with cholesterol.2003In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 84, no 4, p. 2192-206Article in journal (Refereed)
    Abstract [en]

    To investigate the microscopic interactions between cholesterol and lipids in biological membranes, we have performed a series of molecular dynamics simulations of large membranes with different levels of cholesterol content. The simulations extend to 10 ns, and were performed with hydrated dipalmitoylphosphatidylcholine (DPPC) bilayers. The bilayers contain 1024 lipids of which 0-40% were cholesterol and the rest DPPC. The effects of cholesterol on the structure and mesoscopic dynamics of the bilayer were monitored as a function of cholesterol concentration. The main effects observed are a significant ordering of the DPPC chains (as monitored by NMR type order parameters), a reduced fraction of gauche bonds, a reduced surface area per lipid, less undulations--corresponding to an increased bending modulus for the membrane, smaller area fluctuations, and a reduced lateral diffusion of DPPC-lipids as well as cholesterols.

  • 38.
    Hoh, Jan H.
    et al.
    KTH.
    Heinz, William F.
    Johns Hopkins Sch Med, Physiol, Baltimore, MD USA..
    Bacterial Chemotactic Tumble Angles Reduce Backtracking and Maximize Information Gathering2015In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 108, no 2, p. 601A-602AArticle in journal (Other academic)
  • 39.
    Howard, Rebecca J.
    et al.
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Solna, Sweden..
    Fourati, Zaineb
    Inst Pasteur, Unit Struct Dynam Macromol, Paris, France..
    Heusser, Stephanie A.
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Solna, Sweden..
    Hui, Haidai
    Inst Pasteur, Unit Struct Dynam Macromol, Paris, France..
    Ruza, Reinis R.
    Inst Pasteur, Unit Struct Dynam Macromol, Paris, France..
    Sauguet, Ludovic
    Inst Pasteur, Unit Struct Dynam Macromol, Paris, France..
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Physics, Theoretical & Computational Biophysics. Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Solna, Sweden.
    Delarue, Marc
    Inst Pasteur, Unit Struct Dynam Macromol, Paris, France..
    Structural Details of an Allosteric Mechanism for Bimodal Anesthetic Modulation of Pentameric Ligand-Gated Ion Channels2018In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 114, no 3, p. 204A-204AArticle in journal (Other academic)
  • 40. Howard, Rebecca J.
    et al.
    Heusser, Stephanie A.
    Yoluk, Ozge
    KTH, School of Engineering Sciences (SCI), Theoretical Physics.
    Snow, Oliver
    KTH, School of Engineering Sciences (SCI), Theoretical Physics. Stockholm Univ, Sweden.
    Klement, Göran
    KTH, School of Engineering Sciences (SCI), Theoretical Physics. Stockholm Univ, Sweden.
    Mola, Alex R.
    Ruel, Travers M. D.
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Theoretical Physics. Stockholm Univ, Sweden.
    Transmembrane Structural Determinants of Alcohol Binding and Modulation in a Model Ligand-Gated Ion Channel2017In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 112, no 3, p. 554A-554AArticle in journal (Refereed)
  • 41. Howard, Rebecca J.
    et al.
    Murail, Samuel
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Ondricek, Kathryn E.
    Corringer, Pierre-Jean
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Trudell, James R.
    Harris, R. Adron
    Structural Basis For Alcohol Modulation of Pentameric Ligand-Gated Ion Channels2012In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 102, no 3, p. 411A-411AArticle in journal (Other academic)
  • 42. Howard, Rebecca J.
    et al.
    Sauguet, Ludovic
    Brömstrup, Torben
    Swedish e-Science Resarch Centre.
    Murail, Samuel
    Lee, Ui S.
    Horani, Suzzane
    Trudell, James R.
    Corringer, Pierre-Jean
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Delarue, Marc
    Harris, R. Adron
    Alcohol and Anesthetic Binding to Pentameric Ligand-Gated Ion Channels Revealed in a Prokaryotic Model System2013In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 104, no 2, p. 635A-636AArticle in journal (Other academic)
  • 43.
    Howard, Rebecca J.
    et al.
    Stockholm Univ, Dept Biochem & Biophys, Stockholm, Sweden..
    Zhuang, Yuxuan
    Stockholm Univ, Dept Biochem & Biophys, Stockholm, Sweden..
    Heusser, Stephanie A.
    Univ Copenhagen, Dept Drug Design & Pharmacol, Copenhagen, Denmark..
    Bergh, Cathrine
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH Royal Inst Tech, Appl Phys, Stockholm, Sweden..
    Rovsnik, Urska
    Stockholm Univ, Dept Biochem & Biophys, Stockholm, Sweden..
    Orellana, Laura
    Stockholm Univ, Dept Biochem & Biophys, Stockholm, Sweden..
    Lindahl, Erik
    KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, Superseded Departments (pre-2005), Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH Royal Inst Tech, Appl Phys, Stockholm, Sweden..
    Allosteric Gating Determinants in the Transmembrane Domain of Pentameric Ligand-Gated Ion Channels2020In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 118, no 3, p. 584A-584AArticle in journal (Other academic)
  • 44.
    Howard, Rebecca J.
    et al.
    Stockholm Univ, Biochem & Biophys, Stockholm, Sweden..
    Zhuang, Yuxuan
    Uppsala Univ, Chem, Uppsala, Sweden..
    Nakamura, Shinjiro
    KTH, School of Biotechnology (BIO).
    Lycksell, Marie
    Stockholm Univ, Biochem & Biophys, Stockholm, Sweden..
    Kiik, Helen
    SciLifeLab, Biophys, Solna, Sweden..
    Rovsnik, Urska
    Stockholm Univ, Biochem & Biophys, Stockholm, Sweden..
    Bergh, Cathrine
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Heusser, Stephanie A.
    Stockholm Univ, Biochem & Biophys, Stockholm, Sweden..
    Orellana, Laura
    Stockholm Univ, Biochem & Biophys, Stockholm, Sweden..
    Lindahl, Erik
    Stockholm Univ, Biochem & Biophys, Stockholm, Sweden..
    Allosteric Modulation via Transmembrane Interfaces in a Pentameric Ligand-Gated Ion Channel2019In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 116, no 3, p. 245A-246AArticle in journal (Other academic)
  • 45.
    Johansson, Anna C V
    et al.
    Stockholm University.
    Lindahl, Erik
    Stockholm University.
    Amino-acid solvation structure in transmembrane helices from molecular dynamics simulations.2006In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 91, no 12, p. 4450-63Article in journal (Refereed)
    Abstract [en]

    Understanding the solvation of amino acids in biomembranes is an important step to better explain membrane protein folding. Several experimental studies have shown that polar residues are both common and important in transmembrane segments, which means they have to be solvated in the hydrophobic membrane, at least until helices have aggregated to form integral proteins. In this work, we have used computer simulations to unravel these interactions on the atomic level, and classify intramembrane solvation properties of amino acids. Simulations have been performed for systematic mutations in poly-Leu helices, including not only each amino acid type, but also every z-position in a model helix. Interestingly, many polar or charged residues do not desolvate completely, but rather retain hydration by snorkeling or pulling in water/headgroups--even to the extent where many of them exist in a microscopic polar environment, with hydration levels corresponding well to experimental hydrophobicity scales. This suggests that even for polar/charged residues a large part of solvation cost is due to entropy, not enthalpy loss. Both hydration level and hydrogen bonding exhibit clear position-dependence. Basic side chains cause much less membrane distortion than acidic, since they are able to form hydrogen bonds with carbonyl groups instead of water or headgroups. This preference is supported by sequence statistics, where basic residues have increased relative occurrence at carbonyl z-coordinates. Snorkeling effects and N-/C-terminal orientation bias are directly observed, which significantly reduces the effective thickness of the hydrophobic core. Aromatic side chains intercalate efficiently with lipid chains (improving Trp/Tyr anchoring to the interface) and Ser/Thr residues are stabilized by hydroxyl groups sharing hydrogen bonds to backbone oxygens.

  • 46.
    Kasimova, Marina A.
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Lindahl, Erik
    KTH.
    Delemotte, Lucie
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Detection of Voltage-Sensing Residues in Membrane Proteins2018In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 114, no 3, p. 476A-476AArticle in journal (Other academic)
  • 47.
    Kasimova, Marina A.
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH Royal Inst Technol, Dept Appl Phys, Stockholm, Sweden..
    Lynagh, Timothy
    Univ Copenhagen, Copenhagen, Denmark..
    Sheikh, Zeshan Pervez
    Univ Copenhagen, Copenhagen, Denmark..
    Granata, Daniele
    Temple Univ, Inst Computat Mol Sci, Philadelphia, PA 19122 USA..
    Borg, Christian Bernsen
    Univ Copenhagen, Copenhagen, Denmark..
    Carnevale, Vincenzo
    Temple Univ, Inst Computat Mol Sci, Philadelphia, PA 19122 USA..
    Pless, Stephan Alexander
    Univ Copenhagen, Copenhagen, Denmark..
    Evolutionarily Conserved Interactions within the Pore Domain of Acid-Sensing Ion Channels2020In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 118, no 4, p. 861-872Article in journal (Refereed)
    Abstract [en]

    Despite the sequence homology between acid-sensing ion channels (ASICs) and epithelial sodium channel (ENaCs), these channel families display very different functional characteristics. Whereas ASICs are gated by protons and show a relatively low degree of selectivity for sodium over potassium, ENaCs are constitutively active and display a remarkably high degree of sodium selectivity. To decipher if some of the functional diversity originates from differences within the transmembrane helices (M1 and M2) of both channel families, we turned to a combination of computational and functional interrogations, using statistical coupling analysis and mutational studies on mouse ASIC1a. The coupling analysis suggests that the relative position of M1 and M2 in the upper part of the pore domain is likely to remain constant during the ASIC gating cycle, whereas they may undergo relative movements in the lower part. Interestingly, our data suggest that to account for coupled residue pairs being in close structural proximity, both domain-swapped and nondomain-swapped ASIC M2 conformations need to be considered. Such conformational flexibility is consistent with structural work, which suggested that the lower part of M2 can adopt both domain-swapped and nondomain-swapped conformations. Overall, mutations to residues in the middle and lower pore were more likely to affect gating and/or ion selectivity than those in the upper pore. Indeed, disrupting the putative interaction between a highly conserved Trp/Glu residue pair in the lower pore is detrimental to gating and selectivity, although this interaction might occur in both domain-swapped and nonswapped conformations. Finally, our results suggest that the greater number of larger, aromatic side chains in the ENaC M2 helix may contribute to the constitutive activity of these channels at a resting pH. Together, the data highlight differences in the transmembrane domains of these closely related ion channels that may help explain some of their distinct functional properties.

  • 48.
    Kasimova, Marina
    et al.
    KTH, School of Engineering Sciences (SCI), Theoretical Physics.
    Yazici, Aysenur
    Granata, Daniele
    Rohacs, Tibor
    Carnevale, Vincenzo
    Dynamic Solvation of Protein Cavities Underlies TRPV1 Gating2017In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 112, no 3, p. 466A-466AArticle in journal (Refereed)
  • 49.
    Khorshidi, Mohammad A.
    et al.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Vanherberghen, Bruno
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Önfelt, Björn
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Natural Killer Cell-Mediated Tumor Surveillance: Correlation Between Killing Efficiency, Transient Migration Behavior and Morphology2012In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 102, no 3, p. 706A-706AArticle in journal (Other academic)
  • 50. Kimanius, Dari
    et al.
    White, Stephen
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Physics, Theoretical & Computational Biophysics. Stockholm University, Sweden.
    Kaback, Ronald
    Andersson, Magnus
    KTH, School of Engineering Sciences (SCI), Physics, Theoretical & Computational Biophysics.
    Uptake Dynamics in the LacY Membrane Protein Transporter2017In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 112, no 3, p. 128A-128AArticle in journal (Other academic)
123 1 - 50 of 113
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