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  • 1.
    Elias-Wolff, Federico
    et al.
    Stockholm Univ, Dept Biochem & Biophys, Stockholm, Sweden; Stockholm Univ, Dept Mat & Environm Chem, Stockholm, Sweden.
    Lindén, Martin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology.
    Lyubartsev, Alexander P.
    Stockholm Univ, Dept Mat & Environm Chem, Stockholm, Sweden.
    Brandt, Erik G.
    Stockholm Univ, Dept Mat & Environm Chem, Stockholm, Sweden.
    Computing Curvature Sensitivity of Biomolecules in Membranes by Simulated Buckling2018In: Journal of Chemical Theory and Computation, ISSN 1549-9618, E-ISSN 1549-9626, Vol. 14, no 3, p. 1643-1655Article in journal (Refereed)
    Abstract [en]

    Membrane curvature sensing, where the binding free energies of membrane-associated molecules depend on the local membrane curvature, is a key factor to modulate and maintain the shape and organization of cell membranes. However, the microscopic mechanisms are not well understood, partly due to absence of efficient simulation methods. Here, we describe a method to compute the curvature dependence of the binding free energy of a membrane associated probe molecule that interacts with a buckled membrane, which has been created by lateral compression of a flat bilayer patch. This buckling approach samples a wide range of curvatures in a single simulation, and anisotropic effects can be extracted from the orientation statistics. We develop an efficient and robust algorithm to extract the motion of the probe along the buckled membrane surface, and evaluate its numerical properties by extensive sampling of three coarse-grained model systems: local lipid density in a curved environment for single-component bilayers, curvature preferences of individual lipids in two-component membranes, and curvature sensing by a homotrimeric transmembrane protein. The method can be used to complement experimental data from curvature partition assays and provides additional insight into mesoscopic theories and molecular mechanisms for curvature sensing.

  • 2.
    Elias-Wolff, Federico
    et al.
    Stockholm Univ, Dept Biochem & Biophys, Stockholm, Sweden;Stockholm Univ, Dept Mat & Environm Chem, Stockholm, Sweden.
    Lindén, Martin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology. Scania CV AB, Sodertalje, Sweden.
    Lyubartsev, Alexander P.
    Stockholm Univ, Dept Mat & Environm Chem, Stockholm, Sweden.
    Brandt, Erik G.
    Stockholm Univ, Dept Mat & Environm Chem, Stockholm, Sweden.
    Curvature sensing by cardiolipin in simulated buckled membranes2019In: Soft Matter, ISSN 1744-683X, E-ISSN 1744-6848, Vol. 15, no 4, p. 792-802Article in journal (Refereed)
    Abstract [en]

    Cardiolipin is a non-bilayer phospholipid with a unique dimeric structure. It localizes to negative curvature regions in bacteria and is believed to stabilize respiratory chain complexes in the highly curved mitochondrial membrane. Cardiolipin's localization mechanism remains unresolved, because important aspects such as the structural basis and strength for lipid curvature preferences are difficult to determine, partly due to the lack of efficient simulation methods. Here, we report a computational approach to study curvature preferences of cardiolipin by simulated membrane buckling and quantitative modeling. We combine coarse-grained molecular dynamics with simulated buckling to determine the curvature preferences in three-component bilayer membranes with varying concentrations of cardiolipin, and extract curvature-dependent concentrations and lipid acyl chain order parameter profiles. Cardiolipin shows a strong preference for negative curvatures, with a highly asymmetric chain order parameter profile. The concentration profiles are consistent with an elastic model for lipid curvature sensing that relates lipid segregation to local curvature via the material constants of the bilayers. These computations constitute new steps to unravel the molecular mechanism by which cardiolipin senses curvature in lipid membranes, and the method can be generalized to other lipids and membrane components as well.

  • 3. Ge, Changrong
    et al.
    Gómez-Llobregat, Jordi
    Skwark, Marcin J
    Ruysschaert, Jean-Marie
    Wieslander, Ake
    Lindén, Martin
    Membrane remodeling capacity of a vesicle-inducing glycosyltransferase2014In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 281, no 16, p. 3667-3684Article in journal (Refereed)
    Abstract [en]

    Intracellular vesicles are abundant in eukaryotic cells but absent in the Gram-negative bacterium Escherichia coli. However, strong overexpression of a monotopic glycolipid-synthesizing enzyme, monoglucosyldiacylglycerol synthase from Acholeplasma laidlawii (alMGS), leads to massive formation of vesicles in the cytoplasm of E. coli. More importantly, alMGS provides a model system for the regulation of membrane properties by membrane-bound enzymes, which is critical for maintaining cellular integrity. Both phenomena depend on how alMGS binds to cell membranes, which is not well understood. Here, we carry out a comprehensive investigation of the membrane binding of alMGS by combining bioinformatics methods with extensive biochemical studies, structural modeling and molecular dynamics simulations. We find that alMGS binds to the membrane in a fairly upright manner, mainly by residues in the N-terminal domain, and in a way that induces local enrichment of anionic lipids and a local curvature deformation. Furthermore, several alMGS variants resulting from substitution of residues in the membrane anchoring segment are still able to generate vesicles, regardless of enzymatic activity. These results clarify earlier theories about the driving forces for vesicle formation, and shed new light on the membrane binding properties and enzymatic mechanism of alMGS and related monotopic GT-B fold glycosyltransferases.

  • 4.
    Gomez-Llobregat, Jordi
    et al.
    Stockholm Univ, Dept Biochem & Biophys, Ctr Biomembrane Res, S-10691 Stockholm, Sweden..
    Elias-Wolff, Federico
    Stockholm Univ, Dept Biochem & Biophys, Ctr Biomembrane Res, S-10691 Stockholm, Sweden..
    Lindén, Martin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Anisotropic Membrane Curvature Sensing by Amphipathic Peptides2016In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 110, no 1, p. 197-204Article in journal (Refereed)
    Abstract [en]

    Many proteins and peptides have an intrinsic capacity to sense and induce membrane curvature, and play crucial roles for organizing and remodeling cell membranes. However, the molecular driving forces behind these processes are not well understood. Here, we describe an approach to study curvature sensing by simulating the interactions of single molecules with a buckled lipid bilayer. We analyze three amphipathic antimicrobial peptides, a class of membrane-associated molecules that specifically target and destabilize bacterial membranes, and find qualitatively different sensing characteristics that would be difficult to resolve with other methods. Our findings provide evidence for direction-dependent curvature sensing mechanisms in amphipathic peptides and challenge existing theories of hydrophobic insertion. The buckling approach is generally applicable to a wide range of curvature-sensing molecules, and our results provide strong motivation to develop new experimental methods to track position and orientation of membrane proteins.

  • 5.
    Gomez-Llobregat, Jordi
    et al.
    Stockholm Univ, Biochem & Biophys, S-10691 Stockholm, Sweden..
    Lindén, Martin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Anisotropic Membrane Curvature Sensing by Antibacterial Peptides2015In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 108, no 2, p. 550A-550AArticle in journal (Other academic)
  • 6. Ismail, Nurzian
    et al.
    Hedman, Rickard
    Lindén, Martin
    Stockholm University.
    von Heijne, Gunnar
    Charge-driven dynamics of nascent-chain movement through the SecYEG translocon2015In: Nature Structural & Molecular Biology, ISSN 1545-9993, E-ISSN 1545-9985, Vol. 22, p. 145-149Article in journal (Refereed)
    Abstract [en]

    On average, every fifth residue in secretory proteins carries either a positive or a negative charge. In a bacterium such as Escherichia coli, charged residues are exposed to an electric field as they transit through the inner membrane, and this should generate a fluctuating electric force on a translocating nascent chain. Here, we have used translational arrest peptides as in vivo force sensors to measure this electric force during cotranslational chain translocation through the SecYEG translocon. We find that charged residues experience a biphasic electric force as they move across the membrane, including an early component with a maximum when they are 47-49 residues away from the ribosomal P site, followed by a more slowly varying component. The early component is generated by the transmembrane electric potential, whereas the second may reflect interactions between charged residues and the periplasmic membrane surface.

  • 7. Johnson, Stephanie
    et al.
    Lindén, Martin
    Phillips, Rob
    Sequence dependence of transcription factor-mediated DNA looping2012In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 40, no 16, p. 7728-7738Article in journal (Refereed)
    Abstract [en]

    DNA is subject to large deformations in a wide range of biological processes. Two key examples illustrate how such deformations influence the readout of the genetic information: the sequestering of eukaryotic genes by nucleosomes and DNA looping in transcriptional regulation in both prokaryotes and eukaryotes. These kinds of regulatory problems are now becoming amenable to systematic quantitative dissection with a powerful dialogue between theory and experiment. Here, we use a single-molecule experiment in conjunction with a statistical mechanical model to test quantitative predictions for the behavior of DNA looping at short length scales and to determine how DNA sequence affects looping at these lengths. We calculate and measure how such looping depends upon four key biological parameters: the strength of the transcription factor binding sites, the concentration of the transcription factor, and the length and sequence of the DNA loop. Our studies lead to the surprising insight that sequences that are thought to be especially favorable for nucleosome formation because of high flexibility lead to no systematically detectable effect of sequence on looping, and begin to provide a picture of the distinctions between the short length scale mechanics of nucleosome formation and looping.

  • 8. Johnson, Stephanie
    et al.
    van de Meent, Jan-Willem
    Phillips, Rob
    Wiggins, Chris H
    Lindén, Martin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Multiple LacI-mediated loops revealed by Bayesian statistics and tethered particle motion2014In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 42, no 16, p. 10265-10277Article in journal (Refereed)
    Abstract [en]

    The bacterial transcription factor LacI loops DNA by binding to two separate locations on the DNA simultaneously. Despite being one of the best-studied model systems for transcriptional regulation, the number and conformations of loop structures accessible to LacI remain unclear, though the importance of multiple coexisting loops has been implicated in interactions between LacI and other cellular regulators of gene expression. To probe this issue, we have developed a new analysis method for tethered particle motion, a versatile and commonly used in vitro single-molecule technique. Our method, vbTPM, performs variational Bayesian inference in hidden Markov models. It learns the number of distinct states (i.e. DNA-protein conformations) directly from tethered particle motion data with better resolution than existing methods, while easily correcting for common experimental artifacts. Studying short (roughly 100 bp) LacI-mediated loops, we provide evidence for three distinct loop structures, more than previously reported in single-molecule studies. Moreover, our results confirm that changes in LacI conformation and DNA-binding topology both contribute to the repertoire of LacI-mediated loops formed in vitro, and provide qualitatively new input for models of looping and transcriptional regulation. We expect vbTPM to be broadly useful for probing complex protein-nucleic acid interactions.

  • 9.
    Lindén, Martin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology.
    An early peak in ion channel research2018In: Nature Physics, ISSN 1745-2473, E-ISSN 1745-2481, Vol. 14, no 2, p. 105-105Article in journal (Other academic)
  • 10. Lindén, Martin
    Decay times in turnover statistics of single enzymes2008In: Physical Review E. Statistical, Nonlinear, and Soft Matter Physics, ISSN 1539-3755, E-ISSN 1550-2376, Vol. 78, no 1 Pt 1, p. 010901-Article in journal (Refereed)
    Abstract [en]

    The first passage times for enzymatic turnovers in nonequilibrium steady state display a statistical symmetry property related to nonequilibrium fluctuation theorems, which makes it possible to extract the chemical driving force from single molecule trajectories in nonequilibrium steady state. Below, we show that the number of decay constants needed to describe the first passage time distribution of this system is not equal to the number of states in the first passage problem, as one would generally expect. Instead, the structure of the kinetic mechanism makes half of the decay times vanish identically from the turnover time distribution. The terms that cancel out correspond to the eigenvalues of a certain submatrix of the master equation matrix for the first exit time problem. We discuss how these results make modeling and data analysis easier for such systems, and how the turnovers can be measured.

  • 11. Lindén, Martin
    Pulling out the coordination mechanism of myosin-VI2009In: Nature Chemical Biology, ISSN 1552-4450, E-ISSN 1552-4469, Vol. 5, no 6, p. 376-377Article in journal (Other academic)
  • 12.
    Lindén, Martin
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology.
    Curic, Vladimir
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology.
    Amselem, Elias
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology.
    Elf, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology.
    Pointwise error estimates in localization microscopy2017In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 15115Article in journal (Refereed)
    Abstract [en]

    Pointwise localization of individual fluorophores is a critical step in super-resolution localization microscopy and single particle tracking. Although the methods are limited by the localization errors of individual fluorophores, the pointwise localization precision has so far been estimated using theoretical best case approximations that disregard, for example, motion blur, defocus effects and variations in fluorescence intensity. Here, we show that pointwise localization precision can be accurately estimated directly from imaging data using the Bayesian posterior density constrained by simple microscope properties. We further demonstrate that the estimated localization precision can be used to improve downstream quantitative analysis, such as estimation of diffusion constants and detection of changes in molecular motion patterns. Finally, the quality of actual point localizations in live cell super-resolution microscopy can be improved beyond the information theoretic lower bound for localization errors in individual images, by modelling the movement of fluorophores and accounting for their pointwise localization uncertainty.

  • 13.
    Lindén, Martin
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Elf, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Single Molecule Tracking in Living Cells: Multistep Reactions, Simulated Microscopy and New Analysis Methods2015In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 108, no 2, p. 360A-360AArticle in journal (Other academic)
  • 14.
    Lindén, Martin
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology.
    Elf, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology.
    Variational Algorithms for Analyzing Noisy Multistate Diffusion Trajectories2018In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 115, no 2, p. 276-282Article in journal (Refereed)
    Abstract [en]

    Single-particle tracking offers a noninvasive high-resolution probe of biomolecular reactions inside living cells. However, efficient data analysis methods that correctly account for various noise sources are needed to realize the full quantitative potential of the method. We report algorithms for hidden Markov-based analysis of single-particle tracking data, which incorporate most sources of experimental noise, including heterogeneous localization errors and missing positions. Compared to previous implementations, the algorithms offer significant speedups, support for a wider range of inference methods, and a simple user interface. This will enable more advanced and exploratory quantitative analysis of single-particle tracking data.

  • 15. Lindén, Martin
    et al.
    Sens, Pierre
    Phillips, Rob
    Entropic tension in crowded membranes2012In: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 8, no 3, p. e1002431-Article in journal (Refereed)
    Abstract [en]

    Unlike their model membrane counterparts, biological membranes are richly decorated with a heterogeneous assembly of membrane proteins. These proteins are so tightly packed that their excluded area interactions can alter the free energy landscape controlling the conformational transitions suffered by such proteins. For membrane channels, this effect can alter the critical membrane tension at which they undergo a transition from a closed to an open state, and therefore influence protein function in vivo. Despite their obvious importance, crowding phenomena in membranes are much less well studied than in the cytoplasm. Using statistical mechanics results for hard disk liquids, we show that crowding induces an entropic tension in the membrane, which influences transitions that alter the projected area and circumference of a membrane protein. As a specific case study in this effect, we consider the impact of crowding on the gating properties of bacterial mechanosensitive membrane channels, which are thought to confer osmoprotection when these cells are subjected to osmotic shock. We find that crowding can alter the gating energies by more than [Formula: see text] in physiological conditions, a substantial fraction of the total gating energies in some cases. Given the ubiquity of membrane crowding, the nonspecific nature of excluded volume interactions, and the fact that the function of many membrane proteins involve significant conformational changes, this specific case study highlights a general aspect in the function of membrane proteins.

  • 16.
    Lindén, Martin
    et al.
    Theoretical Physics, Royal Institute of Technology, AlbaNova, 10691 Stockholm, Sweden.
    Tuohimaa, Tomi
    Jonsson, Ann-Beth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Wallin, Mats
    Force generation in small ensembles of Brownian motors2006In: Physical Review E. Statistical, Nonlinear, and Soft Matter Physics: Statistical Physics, Plasmas, Fluids, and Related Interdisciplinary Topics, ISSN 1063-651X, E-ISSN 1095-3787, Vol. 74, no 2, p. 021908-1-021908-8Article in journal (Refereed)
    Abstract [en]

    The motility of certain gram-negative bacteria is mediated by retraction of type IV pili surface filaments, which are essential for infectivity. The retraction is powered by a strong molecular motor protein, PilT, producing very high forces that can exceed 150 pN. The molecular details of the motor mechanism are still largely unknown, while other features have been identified, such as the ring-shaped protein structure of the PilT motor. The surprisingly high forces generated by the PilT system motivate a model investigation of the generation of large forces in molecular motors. We propose a simple model, involving a small ensemble of motor subunits interacting through the deformations on a circular backbone with finite stiffness. The model describes the motor subunits in terms of diffusing particles in an asymmetric, time-dependent binding potential (flashing ratchet potential), roughly corresponding to the ATP hydrolysis cycle. We compute force-velocity relations in a subset of the parameter space and explore how the maximum force (stall force) is determined by stiffness, binding strength, ensemble size, and degree of asymmetry. We identify two qualitatively different regimes of operation depending on the relation between ensemble size and asymmetry. In the transition between these two regimes, the stall force depends nonlinearly on the number of motor subunits. Compared to its constituents without interactions, we find higher efficiency and qualitatively different force-velocity relations. The model captures several of the qualitative features obtained in experiments on pilus retraction forces, such as roughly constant velocity at low applied forces and insensitivity in the stall force to changes in the ATP concentration.

  • 17. Lindén, Martin
    et al.
    Wallin, Mats
    Dwell time symmetry in random walks and molecular motors2007In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 92, no 11, p. 3804-3816Article in journal (Refereed)
    Abstract [en]

    The statistics of steps and dwell times in reversible molecular motors differ from those of cycle completion in enzyme kinetics. The reason is that a step is only one of several transitions in the mechanochemical cycle. As a result, theoretical results for cycle completion in enzyme kinetics do not apply to stepping data. To allow correct parameter estimation, and to guide data analysis and experiment design, a theoretical treatment is needed that takes this observation into account. In this article, we model the distribution of dwell times and number of forward and backward steps using first passage processes, based on the assumption that forward and backward steps correspond to different directions of the same transition. We extend recent results for systems with a single cycle and consider the full dwell time distributions as well as models with multiple pathways, detectable substeps, and detachments. Our main results are a symmetry relation for the dwell time distributions in reversible motors, and a relation between certain relative step frequencies and the free energy per cycle. We demonstrate our results by analyzing recent stepping data for a bacterial flagellar motor, and discuss the implications for the efficiency and reversibility of the force-generating subunits.

  • 18.
    Lindén, Martin
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology.
    Ćurić, Vladimir
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology.
    Boucharin, Alexis
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology.
    Fange, David
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology.
    Elf, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology.
    Simulated single molecule microscopy with SMeagol2016In: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 32, no 15, p. 2394-2395Article in journal (Refereed)
    Abstract [en]

    Summary: SMeagol is a software tool to simulate highly realistic microscopy data based on spatial systems biology models, in order to facilitate development, validation and optimization of advanced analysis methods for live cell single molecule microscopy data.

    Availability and implementation: SMeagol runs on Matlab R2014 and later, and uses compiled binaries in C for reaction–diffusion simulations. Documentation, source code and binaries for Mac OS, Windows and Ubuntu Linux can be downloaded from http://smeagol.sourceforge.net.

  • 19.
    Martyna, Agnieszka
    et al.
    Univ Kent, Sch Biosci, Canterbury CT2 7NJ, Kent, England..
    Gomez-Llobregat, Jordi
    Stockholm Univ, Dept Biochem & Biophys, Ctr Biomembrane Res, SE-10691 Stockholm, Sweden..
    Lindén, Martin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology. Stockholm Univ, Dept Biochem & Biophys, Ctr Biomembrane Res, SE-10691 Stockholm, Sweden..
    Rossman, Jeremy S.
    Univ Kent, Sch Biosci, Canterbury CT2 7NJ, Kent, England..
    Curvature Sensing by a Viral Scission Protein2016In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 55, no 25, p. 3493-3496Article in journal (Refereed)
    Abstract [en]

    Membrane scission is the final step in all budding processes wherein a membrane neck is sufficiently constricted so as to allow for fission and the release of the budded particle. For influenza viruses, membrane scission is mediated by an amphipathic helix (AH) domain in the viral M2 protein. While it is known that the M2AH alters membrane curvature, it is not known how the protein is localized to the center neck of budding virions where it would be able to cause membrane scission. Here, we use molecular dynamics simulations on buckled lipid bilayers to show that the M2AH senses membrane curvature and preferentially localizes to regions of high membrane curvature, comparable to that seen at the center neck of budding influenza viruses. These results were then validated using in vitro binding assays to show that the M2AH senses membrane curvature by detecting lipid packing defects in the membrane. Our results show that the M2AH senses membrane curvature and suggest that the AH domain may localize the protein at the viral neck where it can then mediate membrane scission and the release of budding viruses.

  • 20.
    Persson, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Linden, Martin
    Unoson, Cecilia
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Elf, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Extracting intracellular diffusive states and transition rates from single-molecule tracking data2013In: Nature Methods, ISSN 1548-7091, E-ISSN 1548-7105, Vol. 10, no 3, p. 265-269Article in journal (Refereed)
    Abstract [en]

    We provide an analytical tool based on a variational Bayesian treatment of hidden Markov models to combine the information from thousands of short single-molecule trajectories of intracellularly diffusing proteins. The method identifies the number of diffusive states and the state transition rates. Using this method we have created an objective interaction map for Hfq, a protein that mediates interactions between small regulatory RNAs and their mRNA targets.

  • 21. Tsygankov, Denis
    et al.
    Lindén, Martin
    Fisher, Michael E
    Back-stepping, hidden substeps, and conditional dwell times in molecular motors2007In: Physical Review E. Statistical, Nonlinear, and Soft Matter Physics, ISSN 1539-3755, E-ISSN 1550-2376, Vol. 75, no 2 Pt 1, p. 021909-Article in journal (Refereed)
    Abstract [en]

    Processive molecular motors take more-or-less uniformly sized steps, along spatially periodic tracks, mostly forwards but increasingly backwards under loads. Experimentally, the major steps can be resolved clearly within the noise but one knows biochemically that one or more mechanochemical substeps remain hidden in each enzymatic cycle. In order to properly interpret experimental data for back-to-forward step ratios, mean conditional step-to-step dwell times, etc., a first-passage analysis has been developed that takes account of hidden substeps in N -state sequential models. The explicit, general results differ significantly from previous treatments that identify the observed steps with complete mechanochemical cycles; e.g., the mean dwell times tau(+) and tau(-) prior to forward and back steps, respectively, are normally unequal although the dwell times tau(++) and tau(--) between successive forward and back steps are equal. Illustrative (N=2) -state examples display a wide range of behavior. The formulation extends to the case of two or more detectable transitions in a multistate cycle with hidden substeps.

  • 22.
    Volkov, Ivan
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology.
    Aguirre, Javier
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology.
    Lindén, Martin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology.
    Elf, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology.
    Johansson, Magnus
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology.
    In Vivo Measurements of Protein Synthesis Kinetics using Single-Molecule Tracking of E.Coli tRNAS2016In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 110, no 3, p. 351A-351AArticle in journal (Other academic)
  • 23.
    Volkov, Ivan
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology.
    Lindén, Martin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology.
    Aguirre, Javier
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology.
    Ieong, Ka-Weng
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Biology.
    Metelev, Mikhail
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology.
    Elf, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology.
    Johansson, Magnus
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology.
    tRNA tracking for direct measurements of protein synthesis kinetics in live cells2018In: Nature Chemical Biology, ISSN 1552-4450, E-ISSN 1552-4469, Vol. 14, no 6, p. 618-626Article in journal (Refereed)
    Abstract [en]

    Our ability to directly relate results from test-tube biochemical experiments to the kinetics in living cells is very limited. Here we present experimental and analytical tools to directly study the kinetics of fast biochemical reactions in live cells. Dye-labeled molecules are electroporated into bacterial cells and tracked using super-resolved single-molecule microscopy.Trajectories are analyzed by machine-learning algorithms to directly monitor transitions between bound and free states. In particular, we measure the dwell time of tRNAs on ribosomes, and hence achieve direct measurements of translation rates inside living cells at codon resolution. We find elongation rates with tRNA(Phe) that are in perfect agreement with previous indirect estimates, and once fMet-tRNA(fMet) has bound to the 30S ribosomal subunit, initiation of translation is surprisingly fast and does not limit the overall rate of protein synthesis. The experimental and analytical tools for direct kinetics measurements in live cells have applications far beyond bacterial protein synthesis.

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