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  • 1.
    Andersson, Alma E. V.
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Kasimova, Marina A.
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Delemotte, Lucie
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Exploring the Viral Channel Kcv(PBCV-1) Function via Computation2018In: Journal of Membrane Biology, ISSN 0022-2631, E-ISSN 1432-1424, Vol. 251, no 3, p. 419-430Article in journal (Refereed)
    Abstract [en]

    Viral potassium channels (Kcv) are homologous to the pore module of complex -selective ion channels of cellular organisms. Due to their relative simplicity, they have attracted interest towards understanding the principles of conduction and channel gating. In this work, we construct a homology model of the open state, which we validate by studying the binding of known blockers and by monitoring ion conduction through the channel. Molecular dynamics simulations of this model reveal that the re-orientation of selectivity filter carbonyl groups coincides with the transport of potassium ions, suggesting a possible mechanism for fast gating. In addition, we show that the voltage sensitivity of this mechanism can originate from the relocation of potassium ions inside the selectivity filter. We also explore the interaction of with the surrounding bilayer and observe the binding of lipids in the area between two adjacent subunits. The model is available to the scientific community to further explore the structure/function relationship of Kcv channels.

  • 2.
    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.

  • 3.
    Kasimova, Marina A.
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences (SCI), Applied Physics.
    Lindahl, Erik
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences (SCI), Applied Physics.
    Delemotte, L.
    KTH, School of Engineering Sciences (SCI), Applied Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Determining the molecular basis of voltage sensitivity in membrane proteins2018In: The Journal of General Physiology, ISSN 0022-1295, E-ISSN 1540-7748, Vol. 215, no 10, p. 1444-1458Article in journal (Refereed)
    Abstract [en]

    Voltage-sensitive membrane proteins are united by their ability to transform changes in membrane potential into mechanical work. They are responsible for a spectrum of physiological processes in living organisms, including electrical signaling and cell-cycle progression. Although the mechanism of voltage-sensing has been well characterized for some membrane proteins, including voltage-gated ion channels, even the location of the voltage-sensing elements remains unknown for others. Moreover, the detection of these elements by using experimental techniques is challenging because of the diversity of membrane proteins. Here, we provide a computational approach to predict voltage-sensing elements in any membrane protein, independent of its structure or function. It relies on an estimation of the propensity of a protein to respond to changes in membrane potential. We first show that this property correlates well with voltage sensitivity by applying our approach to a set of voltage-sensitive and voltage-insensitive membrane proteins. We further show that it correctly identifies authentic voltage-sensitive residues in the voltage-sensor domain of voltage-gated ion channels. Finally, we investigate six membrane proteins for which the voltage-sensing elements have not yet been characterized and identify residues and ions that might be involved in the response to voltage. The suggested approach is fast and simple and enables a characterization of voltage sensitivity that goes beyond mere identification of charges. We anticipate that its application before mutagenesis experiments will significantly reduce the number of potential voltage-sensitive elements to be tested. 

  • 4.
    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)
  • 5.
    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.

  • 6.
    Kasimova, Marina A.
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Tewari, Debanjan
    Univ Wisconsin, Dept Neurosci, Madison, WI 53706 USA..
    Cowgill, John B.
    Univ Wisconsin, Dept Neurosci, Madison, WI 53706 USA.;Univ Wisconsin, Grad Program Biophys, Madison, WI USA..
    Ursuleaz, Willy Carrasquel
    Univ Wisconsin, Dept Neurosci, Madison, WI 53706 USA..
    Lin, Jenna L.
    Univ Wisconsin, Dept Neurosci, Madison, WI 53706 USA.;Univ Wisconsin, Grad Program Biophys, Madison, WI USA..
    Delemotte, Lucie
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Chanda, Baron
    Univ Wisconsin, Dept Neurosci, Madison, WI 53706 USA.;Univ Wisconsin, Dept Biomol Chem, Madison, WI 53706 USA..
    Helix breaking transition in the S4 of HCN channel is critical for hyperpolarization- dependent gating2019In: eLIFE, E-ISSN 2050-084X, Vol. 8, article id e53400Article in journal (Refereed)
    Abstract [en]

    In contrast to most voltage-gated ion channels, hyperpolarization- and cAMP gated (HCN) ion channels open on hyperpolarization. Structure-function studies show that the voltagesensor of HCN channels are unique but the mechanisms that determine gating polarity remain poorly understood. All-atom molecular dynamics simulations (similar to 20 mu s) of HCN1 channel under hyperpolarization reveals an initial downward movement of the S4 voltage-sensor but following the transfer of last gating charge, the S4 breaks into two sub-helices with the lower sub-helix becoming parallel to the membrane. Functional studies on bipolar channels show that the gating polarity strongly correlates with helical turn propensity of the substituents at the breakpoint. Remarkably, in a proto-HCN background, the replacement of breakpoint serine with a bulky hydrophobic amino acid is sufficient to completely flip the gating polarity from inward to outward-rectifying. Our studies reveal an unexpected mechanism of inward rectification involving a linker sub-helix emerging from HCN S4 during hyperpolarization.

  • 7.
    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)
  • 8.
    Roose, Benjamin W.
    et al.
    Univ Penn, Dept Chem, 231 S 34th St, Philadelphia, PA 19104 USA..
    Zemerov, Serge D.
    Univ Penn, Dept Chem, 231 S 34th St, Philadelphia, PA 19104 USA..
    Wang, Yanfei
    Harvard Med Sch, 300 Longwood Ave, Boston, MA 02115 USA..
    Kasimova, Marina A.
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Carnevale, Vincenzo
    Temple Univ, Coll Sci & Technol, Inst Computat Mol Sci, 1925 N 12th St, Philadelphia, PA 19122 USA..
    Dmochowski, Ivan J.
    Univ Penn, Dept Chem, 231 S 34th St, Philadelphia, PA 19104 USA..
    A Structural Basis for Xe-129 Hyper-CEST Signal in TEM-1 beta-Lactamase2019In: ChemPhysChem, ISSN 1439-4235, E-ISSN 1439-7641, Vol. 20, no 2, p. 260-267Article in journal (Refereed)
    Abstract [en]

    Genetically encoded (GE) contrast agents detectable by magnetic resonance imaging (MRI) enable non-invasive visualization of gene expression and cell proliferation at virtually unlimited penetration depths. Using hyperpolarized Xe-129 in combination with chemical exchange saturation transfer, an MR contrast approach known as hyper-CEST, enables ultrasensitive protein detection and biomolecular imaging. GE MRI contrast agents developed to date include nanoscale proteinaceous gas vesicles as well as the monomeric bacterial proteins TEM-1 beta-lactamase (bla) and maltose binding protein (MBP). To improve understanding of hyper-CEST NMR with proteins, structural and computational studies were performed to further characterize the Xe-bla interaction. X-ray crystallography validated the location of a high-occupancy Xe binding site predicted by MD simulations, and mutagenesis experiments confirmed this Xe site as the origin of the observed CEST contrast. Structural studies and MD simulations with representative bla mutants offered additional insight regarding the relationship between local protein structure and CEST contrast.

1 - 8 of 8
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