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    Modification of C-Terminus Provides New Insights into the Mechanism of α-Synuclein Aggregation.
    Biophys J 2017 Sep 19. Epub 2017 Sep 19.
    Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic. Electronic address:
    Aggregation of neuronal protein α-synuclein leads to the formation of amyloid fibrils, which are associated with the development of Parkinson's disease. The mechanism of α-synuclein pathology is not fully understood and is a subject of active research in the field. To tackle this problem, the fusions of fluorescent proteins to α-synuclein C-terminus are often used in cellular and animal studies. Read More

    Sites Contributing to TRPA1 Activation by the Anesthetic Propofol Identified by Photoaffinity Labeling.
    Biophys J 2017 Sep 19. Epub 2017 Sep 19.
    Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts. Electronic address:
    In addition to inducing anesthesia, propofol activates a key component of the pain pathway, the transient receptor potential ankyrin 1 ion channel (TRPA1). Recent mutagenesis studies suggested a potential activation site within the transmembrane domain, near the A-967079 cavity. However, mutagenesis cannot distinguish between protein-based and ligand-based mechanisms, nor can this site explain the complex modulation by propofol. Read More

    Functional Validation of Heteromeric Kainate Receptor Models.
    Biophys J 2017 Sep 19. Epub 2017 Sep 19.
    Department of Biochemistry, University of Oxford, Oxford, United Kingdom. Electronic address:
    Kainate receptors require the presence of external ions for gating. Most work thus far has been performed on homomeric GluK2 but, in vivo, kainate receptors are likely heterotetramers. Agonists bind to the ligand-binding domain (LBD) which is arranged as a dimer of dimers as exemplified in homomeric structures, but no high-resolution structure currently exists of heteromeric kainate receptors. Read More

    Molecular Mechanisms of the R61T Mutation in Apolipoprotein E4: A Dynamic Rescue.
    Biophys J 2017 Sep 12. Epub 2017 Sep 12.
    Biochemistry and Biophysics Department, University of North Carolina, Chapel Hill, North Carolina. Electronic address:
    The apolipoprotein E4 (ApoE4) gene is the strongest genetic risk factor for Alzheimer's disease (AD). With respect to the other common isoforms of this protein (ApoE2 and ApoE3), ApoE4 is characterized by lower stability that underlies the formation of a stable interaction between the protein's N- and C-terminal domains. AD-related cellular dysfunctions have been linked to this ApoE4 misfolded state. Read More

    sw ApoMb Amyloid Aggregation under Nondenaturing Conditions: The Role of Native Structure Stability.
    Biophys J 2017 Sep;113(5):991-1001
    Institute of Protein Research, Russian Academy of Sciences, Pushchino, Moscow Region, Russia. Electronic address:
    Investigation of the molecular mechanisms underlying amyloid-related human diseases attracts close attention. These diseases, the number of which currently is above 40, are characterized by formation of peptide or protein aggregates containing a cross-β structure. Most of the amyloidogenesis mechanisms described so far are based on experimental studies of aggregation of short peptides, intrinsically disordered proteins, or proteins under denaturing conditions, and studies of amyloid aggregate formations by structured globular proteins under conditions close to physiological ones are still in the initial stage. Read More

    H4 Tails Potentially Produce the Diversity in the Orientation of Two Nucleosomes.
    Biophys J 2017 Sep;113(5):978-990
    Molecular Modeling and Simulation Group, Department of Quantum Beam Life Science, National Institutes for Quantum and Radiological Science and Technology, Kizugawa, Kyoto, Japan.
    Histone tails play an important role in internucleosomal interaction and chromatin compaction. To understand how the H4 tails are involved in the internucleosomal interaction, an adaptively biased molecular dynamics simulation of 63 models of two stacked nucleosomes, each with the H4 tails in different locations, was carried out. This simulation generated a variety of orientations of the separated nucleosomes depending on the formation of the H4 tail bridge between the H4 tails and the DNA of the neighboring nucleosomes. Read More

    Factors Diminishing Cytoadhesion of Red Blood Cells Infected by Plasmodium falciparum in Arterioles.
    Biophys J 2017 Sep;113(5):1163-1172
    School of Engineering, Tohoku University, Sendai, Japan. Electronic address:
    Cytoadhesion of red blood cells infected by Plasmodium falciparum (Pf-IRBCs) is predominantly found in postcapillary venules, rather than in arterioles. However, factors influencing this phenomenon remain unclear. Here, we conduct a systematic study using a numerical model coupling the fluid and solid mechanics of the cells and cellular environment with the biochemical ligand-receptor interaction. Read More

    Acceleration Strategies to Enhance Metabolic Ensemble Modeling Performance.
    Biophys J 2017 Sep;113(5):1150-1162
    Department of Chemical and Biological Engineering, Northwestern University, Evanston, Illinois. Electronic address:
    Developing reliable, predictive kinetic models of metabolism is a difficult, yet necessary, priority toward understanding and deliberately altering cellular behavior. Constraint-based modeling has enabled the fields of metabolic engineering and systems biology to make great strides in interrogating cellular metabolism but does not provide sufficient insight into regulation or kinetic limitations of metabolic pathways. Moreover, the growth-optimized assumptions that constraint-based models often rely on do not hold when studying stationary or persistor cell populations. Read More

    Wave Mechanics of the Vestibular Semicircular Canals.
    Biophys J 2017 Sep;113(5):1133-1149
    Department of Bioengineering, University of Utah, Salt Lake City, Utah; Department of Otolaryngology, University of Utah, Salt Lake City, Utah; Marine Biological Laboratory, Woods Hole, Massachusetts.
    The semicircular canals are biomechanical sensors responsible for detecting and encoding angular motion of the head in 3D space. Canal afferent neurons provide essential inputs to neural circuits responsible for representation of self-position/orientation in space, and to compensatory circuits including the vestibulo-ocular and vestibulo-collic reflex arcs. In this work we derive, to our knowledge, a new 1D mathematical model quantifying canal biomechanics based on the morphology, dynamics of the inner ear fluids, and membranous labyrinth deformability. Read More

    Enhanced Dynamics of Confined Cytoskeletal Filaments Driven by Asymmetric Motors.
    Biophys J 2017 Sep;113(5):1121-1132
    Theoretical Soft Matter and Biophysics, Institute of Complex Systems and Institute for Advanced Simulation, Forschungszentrum Jülich, Jülich, Germany.
    Cytoskeletal filaments and molecular motors facilitate the micron-scale force generation necessary for the distribution of organelles and the restructuring of the cytoskeleton within eukaryotic cells. Although the mesoscopic structure and the dynamics of such filaments have been studied in vitro and in vivo, their connection with filament polarity-dependent motor-mediated force generation is not well understood. Using 2D Brownian dynamics simulations, we study a dense, confined mixture of rigid microtubules (MTs) and active springs that have arms that cross-link neighboring MT pairs and move unidirectionally on the attached MT. Read More

    Spatially Different Tissue-Scale Diffusivity Shapes ANGUSTIFOLIA3 Gradient in Growing Leaves.
    Biophys J 2017 Sep;113(5):1109-1120
    Okazaki Institute for Integrative Bioscience, School of Life Science, Graduate University for Advanced Studies (SOKENDAI), Okazaki, Aichi, Japan; Department of Biological Sciences, Graduate School of Science, University of Tokyo, Tokyo, Japan.
    The spatial gradient of signaling molecules is pivotal for establishing developmental patterns of multicellular organisms. It has long been proposed that these gradients could arise from the pure diffusion process of signaling molecules between cells, but whether this simplest mechanism establishes the formation of the tissue-scale gradient remains unclear. Plasmodesmata are unique channel structures in plants that connect neighboring cells for molecular transport. Read More

    Spatially Organized β-Cell Subpopulations Control Electrical Dynamics across Islets of Langerhans.
    Biophys J 2017 Sep;113(5):1093-1108
    Department of Bioengineering, University of Colorado, Aurora, Colorado; Barbara Davis Center for Diabetes, University of Colorado, Aurora, Colorado. Electronic address:
    Understanding how heterogeneous cells within a multicellular system interact and affect overall function is difficult without a means of perturbing individual cells or subpopulations. Here we apply optogenetics to understand how subpopulations of β-cells control the overall [Ca(2+)]i response and insulin secretion dynamics of the islets of Langerhans. We spatiotemporally perturbed electrical activity in β-cells of channelrhodopsin2-expressing islets, mapped the [Ca(2+)]i response, and correlated this with the cellular metabolic activity and an in silico electrophysiology model. Read More

    β1-Integrin-Mediated Adhesion Is Lipid-Bilayer Dependent.
    Biophys J 2017 Sep;113(5):1080-1092
    Intercollege Graduate Degree Program in Bioengineering and Department of Biomedical Engineering, The Pennsylvania State University, University Park, Pennsylvania. Electronic address:
    Integrin-mediated adhesion is a central feature of cellular adhesion, locomotion, and endothelial cell mechanobiology. Although integrins are known to be transmembrane proteins, little is known about the role of membrane biophysics and dynamics in integrin adhesion. We treated human aortic endothelial cells with exogenous amphiphiles, shown previously in model membranes, and computationally, to affect bilayer thickness and lipid phase separation, and subsequently measured single-integrin-molecule adhesion kinetics using an optical trap, and diffusion using fluorescence correlation spectroscopy. Read More

    Adaptive Response of Actin Bundles under Mechanical Stress.
    Biophys J 2017 Sep;113(5):1072-1079
    CNRS, Laboratoire Physico Chimie Curie, Institut Curie, PSL Research University, Paris, France; Sorbonne Universités, UPMC University Paris 06, Paris, France. Electronic address:
    Actin is one of the main components of the architecture of cells. Actin filaments form different polymer networks with versatile mechanical properties that depend on their spatial organization and the presence of cross-linkers. Here, we investigate the mechanical properties of actin bundles in the absence of cross-linkers. Read More

    Rupture Dynamics and Chromatin Herniation in Deformed Nuclei.
    Biophys J 2017 Sep;113(5):1060-1071
    Department of Materials and Interfaces, Weizmann Institute of Science, Rehovot, Israel.
    During migration of cells in vivo, in both pathological processes such as cancer metastasis or physiological events such as immune cell migration through tissue, the cells must move through narrow interstitial spaces that can be smaller than the nucleus. This can induce deformation of the nucleus which, according to recent experiments, may result in rupture of the nuclear envelope that can lead to cell death, if not prevented or healed within an appropriate time. The nuclear envelope, which can be modeled as a double lipid bilayer attached to a viscoelastic gel (lamina) whose elasticity and viscosity primarily depend on the lamin composition, may utilize mechanically induced, self-healing mechanisms that allow the hole to be closed after the deformation-induced strains are reduced by leakage of the internal fluid. Read More

    Caveolae in Rabbit Ventricular Myocytes: Distribution and Dynamic Diminution after Cell Isolation.
    Biophys J 2017 Sep;113(5):1047-1059
    Institute for Experimental Cardiovascular Medicine, University Heart Center Freiburg-Bad Krozingen, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
    Caveolae are signal transduction centers, yet their subcellular distribution and preservation in cardiac myocytes after cell isolation are not well documented. Here, we quantify caveolae located within 100 nm of the outer cell surface membrane in rabbit single-ventricular cardiomyocytes over 8 h post-isolation and relate this to the presence of caveolae in intact tissue. Hearts from New Zealand white rabbits were either chemically fixed by coronary perfusion or enzymatically digested to isolate ventricular myocytes, which were subsequently fixed at 0, 3, and 8 h post-isolation. Read More

    Microparticle Assembly Pathways on Lipid Membranes.
    Biophys J 2017 Sep;113(5):1037-1046
    Biological and Soft Matter Physics, Huygens-Kamerlingh Onnes Laboratory, Leiden University, Leiden, the Netherlands. Electronic address:
    Understanding interactions between microparticles and lipid membranes is of increasing importance, especially for unraveling the influence of microplastics on our health and environment. Here, we study how a short-ranged adhesive force between microparticles and model lipid membranes causes membrane-mediated particle assembly. Using confocal microscopy, we observe the initial particle attachment to the membrane, then particle wrapping, and in rare cases spontaneous membrane tubulation. Read More

    Two Cl Ions and a Glu Compete for a Helix Cage in the CLC Proton/Cl(-) Antiporter.
    Biophys J 2017 Sep;113(5):1025-1036
    Biochemistry Ph.D. Program, The Graduate Center of the City University of New York; Physics Department, The City College of New York of the City University of New York, New York, New York. Electronic address:
    The ubiquitously expressed CLC chloride transporters are involved in a great variety of physiological functions. The CLC protein fold is shared by Cl(-) channels and 2Cl(-):1H(+) antiporters. The antiporters pump three charges per cycle across the membrane with two Cl ions moving in the opposite direction of one proton. Read More

    Conformational Heterogeneity and FRET Data Interpretation for Dimensions of Unfolded Proteins.
    Biophys J 2017 Sep;113(5):1012-1024
    Departments of Biochemistry and Molecular Genetics, University of Toronto, Toronto, Ontario, Canada. Electronic address:
    A mathematico-physically valid formulation is required to infer properties of disordered protein conformations from single-molecule Förster resonance energy transfer (smFRET). Conformational dimensions inferred by conventional approaches that presume a homogeneous conformational ensemble can be unphysical. When all possible-heterogeneous as well as homogeneous-conformational distributions are taken into account without prejudgment, a single value of average transfer efficiency 〈E〉 between dyes at two chain ends is generally consistent with highly diverse, multiple values of the average radius of gyration 〈Rg〉. Read More

    Effect of a Paramagnetic Spin Label on the Intrinsically Disordered Peptide Ensemble of Amyloid-β.
    Biophys J 2017 Sep;113(5):1002-1011
    Department of Chemical and Biomolecular Engineering, University of California, Berkeley, Berkeley, California; Department of Chemistry, University of California, Berkeley, Berkeley, California; Department of Bioengineering, University of California, Berkeley, Berkeley, California; Pitzer Center for Theoretical Chemistry, University of California, Berkeley, Berkeley, California. Electronic address:
    Paramagnetic relaxation enhancement is an NMR technique that has yielded important insight into the structure of folded proteins, although the perturbation introduced by the large spin probe might be thought to diminish its usefulness when applied to characterizing the structural ensembles of intrinsically disordered proteins (IDPs). We compare the computationally generated structural ensembles of the IDP amyloid-β42 (Aβ42) to an alternative sequence in which a nitroxide spin label attached to cysteine has been introduced at its N-terminus. Based on this internally consistent computational comparison, we find that the spin label does not perturb the signature population of the β-hairpin formed by residues 16-21 and 29-36 that is dominant in the Aβ42 reference ensemble. Read More

    Biophysics of Biochemical Signaling in Dendritic Spines: Implications in Synaptic Plasticity.
    Biophys J 2017 Aug 30. Epub 2017 Aug 30.
    Max Planck Florida Institute for Neuroscience, Jupiter, Florida. Electronic address:
    Dendritic spines are mushroom-shaped postsynaptic compartments that host biochemical signal cascades important for synaptic plasticity and, ultimately, learning and memory. Signaling events in spines involve a signaling network composed of hundreds of signaling proteins interacting with each other extensively. Synaptic plasticity is typically induced by Ca(2+) elevation in spines, which activates a variety of signaling pathways. Read More

    Two Pools of Vesicles Associated with Synaptic Ribbons are Molecularly Prepared for Release.
    Biophys J 2017 Aug 29. Epub 2017 Aug 29.
    Department of Neurobiology and Anatomy, McGovern Medical School, University of Texas Health Science Center at Houston (UTHealth), Houston, Texas; The University of Texas MD Anderson Cancer Center, UTHealth Graduate School of Biomedical Sciences, Houston, Texas. Electronic address:
    Neurons that form ribbon-style synapses are specialized for continuous exocytosis. To this end, their synaptic terminals contain numerous synaptic vesicles, some of which are ribbon associated, that have difference susceptibilities for undergoing Ca(2+)-dependent exocytosis. In this study, we probed the relationship between previously defined vesicle populations and determined their fusion competency with respect to SNARE complex formation. Read More

    Unitary Properties of AMPA Receptors with Reduced Desensitization.
    Biophys J 2017 Aug 29. Epub 2017 Aug 29.
    Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut. Electronic address:
    Wild-type AMPA receptors display a characteristic rapidly desensitizing phenotype. Many studies point to the dimer interface between pairs of extracellular ligand binding domains as the key region controlling the rate at which the receptors desensitize. However, mutations at the extracellular end of the pore-forming regions (near the putative ion channel gate) have also been shown to alter desensitization. Read More

    The Challenge of Interpreting Glutamate-Receptor Ion-Channel Structures.
    Biophys J 2017 Aug 24. Epub 2017 Aug 24.
    Molecular Physiology and Biophysics Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland. Electronic address:
    Ion channels activated by glutamate mediate excitatory synaptic transmission in the central nervous system. Similar to other ligand-gated ion channels, their gating cycle begins with transitions from a ligand-free closed state to glutamate-bound active and desensitized states. In an attempt to reveal the molecular mechanisms underlying gating, numerous structures for glutamate receptors have been solved in complexes with agonists, antagonists, allosteric modulators, and auxiliary proteins. Read More

    Epithelial Monolayers Coalesce on a Viscoelastic Substrate through Redistribution of Vinculin.
    Biophys J 2017 Aug 24. Epub 2017 Aug 24.
    Mechanobiology Institute of Singapore, National University of Singapore, Singapore, Singapore; Center for BioImaging Sciences, Department of Biological Sciences, National University of Singapore, Singapore, Singapore. Electronic address:
    The mechanical properties of the microenvironment play a large role in influencing cellular behavior. In particular, the tradeoff between substrate viscosity and elasticity on collective cell migration by adherent cells is highly physiologically relevant, but remains poorly understood. To investigate the specific effects of viscous substrates, we plated epithelial monolayers onto polydimethylsiloxane substrata with a range of viscosities and elasticities. Read More

    Passive and Active Microrheology of the Intestinal Fluid of the Larval Zebrafish.
    Biophys J 2017 Aug;113(4):957-965
    Department of Physics, Institute of Molecular Biology, Materials Science Institute, University of Oregon, Eugene, Oregon. Electronic address:
    The fluids of the intestine serve as a physical barrier to pathogens, a medium for the diffusion of nutrients and metabolites, and an environment for commensal microbes. The rheological properties of intestinal mucus have therefore been the subject of many investigations, thus far limited to in vitro studies due to the difficulty of measurement in the natural context of the gut. This limitation especially hinders our understanding of how the gut microbiota interact with the intestinal space, since examination of this calls not only for in vivo measurement techniques, but for techniques that can be applied to model organisms in which the microbial state of the gut can be controlled. Read More

    α-Actinin Induces a Kink in the Transmembrane Domain of β3-Integrin and Impairs Activation via Talin.
    Biophys J 2017 Aug;113(4):948-956
    Molecular Cell Biomechanics Laboratory, Departments of Bioengineering and Mechanical Engineering, University of California, Berkeley, Berkeley, California. Electronic address:
    Integrin-mediated signaling is crucial for cell-substrate adhesion and can be triggered from both intra- and extracellular interactions. Although talin binding is sufficient for inside-out activation of integrin, other cytoplasmic proteins such as α-actinin and filamin can directly interfere with talin-mediated integrin activation. Specifically, α-actinin plays distinct roles in regulating αIIbβ3 versus α5β1 integrin. Read More

    Myosin Clusters of Finite Size Develop Contractile Stress in 1D Random Actin Arrays.
    Biophys J 2017 Aug;113(4):937-947
    Courant Institute of Mathematical Sciences, New York University, New York, New York; Department of Biology, New York University, New York, New York. Electronic address:
    Myosin-powered force generation and contraction in nonmuscle cells underlies many cell biological processes and is based on contractility of random actin arrays. This contractility must rely on a microscopic asymmetry, the precise mechanism of which is not completely clear. A number of models of mechanical and structural asymmetries in actomyosin contraction have been posited. Read More

    Mechanics of Fluid-Filled Interstitial Gaps. II. Gap Characteristics in Xenopus Embryonic Ectoderm.
    Biophys J 2017 Aug;113(4):923-936
    Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario, Canada. Electronic address:
    The ectoderm of the Xenopus embryo is permeated by a network of channels that appear in histological sections as interstitial gaps. We characterized this interstitial space by measuring gap sizes, angles formed between adjacent cells, and curvatures of cell surfaces at gaps. From these parameters, and from surface-tension values measured previously, we estimated the values of critical mechanical variables that determine gap sizes and shapes in the ectoderm, using a general model of interstitial gap mechanics. Read More

    Mechanics of Fluid-Filled Interstitial Gaps. I. Modeling Gaps in a Compact Tissue.
    Biophys J 2017 Aug;113(4):913-922
    Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario, Canada. Electronic address:
    Fluid-filled interstitial gaps are a common feature of compact tissues held together by cell-cell adhesion. Although such gaps can in principle be the result of weak, incomplete cell attachment, adhesion is usually too strong for this to occur. Using a mechanical model of tissue cohesion, we show that, instead, a combination of local prevention of cell adhesion at three-cell junctions by fluidlike extracellular material and a reduction of cortical tension at the gap surface are sufficient to generate stable gaps. Read More

    Prospects for Human Erythrocyte Skeleton-Bilayer Dissociation during Splenic Flow.
    Biophys J 2017 Aug;113(4):900-912
    Department of Structural Engineering, University of California, San Diego, La Jolla, California. Electronic address:
    Prospects of vesiculation occurring during splenic flow of erythrocytes are addressed via model simulations of RBC flow through the venous slits of the human spleen. Our model is multiscale and contains a thermally activated rate-dependent description of the entropic elasticity of the RBC spectrin cytoskeleton, including domain unfolding/refolding. Our model also includes detail of the skeleton attachment to the fluidlike lipid bilayer membrane, including a specific accounting for the expansion/contraction of the skeleton that may occur via anchor protein diffusive motion, that is, band 3 and glycophorin, through the membrane. Read More

    Crystal Structure of Leiomodin 2 in Complex with Actin: A Structural and Functional Reexamination.
    Biophys J 2017 Aug;113(4):889-899
    Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address:
    Leiomodins (Lmods) are a family of actin filament nucleators related to tropomodulins (Tmods), which are pointed end-capping proteins. Whereas Tmods have alternating tropomyosin- and actin-binding sites (TMBS1, ABS1, TMBS2, ABS2), Lmods lack TMBS2 and half of ABS1, and present a C-terminal extension containing a proline-rich domain and an actin-binding Wiskott-Aldrich syndrome protein homology 2 (WH2) domain that is absent in Tmods. Most of the nucleation activity of Lmods resides within a fragment encompassing ABS2 and the C-terminal extension. Read More

    Omecamtiv Mecarbil Abolishes Length-Mediated Increase in Guinea Pig Cardiac Myofiber Ca(2+) Sensitivity.
    Biophys J 2017 Aug;113(4):880-888
    Department of Integrative Physiology and Neuroscience (IPN), Washington State University, Pullman, Washington. Electronic address:
    Omecamtiv mecarbil (OM) is a pharmacological agent that augments cardiac contractile function by enhancing myofilament Ca(2+) sensitivity. Given that interventions that increase myofilament Ca(2+) sensitivity have the potential to alter length-dependent activation (LDA) of cardiac myofilaments, we tested the influence of OM on this fundamental property of the heart. This is significant not only because LDA is prominent in cardiac muscle but also because it contributes to the Frank-Starling law, a mechanism by which the heart increases stroke volume in response to an increase in venous return. Read More

    Determination of the Membrane Translocation pK of the pH-Low Insertion Peptide.
    Biophys J 2017 Aug;113(4):869-879
    Department of Biochemistry & Cellular and Molecular Biology, University of Tennessee, Knoxville, Tennessee. Electronic address:
    The pH-low insertion peptide (pHLIP) is a leading peptide technology to target the extracellular acidosis that characterizes solid tumors. The pHLIP binds to lipid membranes, and responds to acidification by undergoing a coupled folding/membrane insertion process. In the final transmembrane state, the C terminus of pHLIP gets exposed to the cytoplasm of the target cell, providing a means to translocate membrane-impermeable drug cargoes across the plasma membrane of cancer cells. Read More

    Does Ceramide Form Channels? The Ceramide-Induced Membrane Permeabilization Mechanism.
    Biophys J 2017 Aug;113(4):860-868
    Biofisika Institute (CSIC, UPV/EHU) and Department of Biochemistry, University of the Basque Country, Leioa, Spain. Electronic address:
    Ceramide is a sphingolipid involved in several cellular processes, including apoptosis. It has been proposed that ceramide forms large and stable channels in the mitochondrial outer membrane that induce cell death through direct release of cytochrome c. However, this mechanism is still debated because the membrane permeabilizing activity of ceramide remains poorly understood. Read More

    Divide & Conquer: Surfactant Protein SP-C and Cholesterol Modulate Phase Segregation in Lung Surfactant.
    Biophys J 2017 Aug;113(4):847-859
    Department of Biochemistry, Faculty of Biology, Complutense University, Madrid, Spain; Healthcare Research Institute of Hospital 12 de Octubre, Hospital Universitario 12 de Octubre, Madrid, Spain. Electronic address:
    Lung surfactant (LS) is an essential system supporting the respiratory function. Cholesterol can be deleterious for LS function, a condition that is reversed by the presence of the lipopeptide SP-C. In this work, the structure of LS-mimicking membranes has been analyzed under the combined effect of SP-C and cholesterol by deuterium NMR and phosphorus NMR and by electron spin resonance. Read More

    Spontaneous Membrane Translocating Peptides: The Role of Leucine-Arginine Consensus Motifs.
    Biophys J 2017 Aug;113(4):835-846
    Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, Louisiana. Electronic address:
    We previously used an orthogonal high-throughput screen to select peptides that spontaneously cross synthetic lipid bilayers without bilayer disruption. Many of the 12-residue spontaneous membrane translocating peptides (SMTPs) selected from the library contained a 5-residue consensus motif, LRLLR in positions 5-9. We hypothesized that the conserved motif could be a necessary and sufficient minimal motif for translocation. Read More

    Conversion of OprO into an OprP-like Channel by Exchanging Key Residues in the Channel Constriction.
    Biophys J 2017 Aug;113(4):829-834
    Department of Life Sciences and Chemistry, Jacobs University Bremen, Bremen, Germany.
    Under phosphate-limiting conditions, the channels OprP and OprO are induced and expressed in the outer membrane of Pseudomonas aeruginosa. Despite their large homology, the phosphate-specific OprP and the diphosphate-specific OprO pores show structural differences in their binding sites situated in the constriction region. Previously, it was shown that the mutation of amino acids in OprP (Y62F and Y114D) led to an exchange in substrate specificity similar to OprO. Read More

    Protonation-State-Dependent Communication in Cytochrome c Oxidase.
    Biophys J 2017 Aug;113(4):817-828
    Institute of Theoretical Physics, Free University Berlin, Berlin, Germany. Electronic address:
    Proton transfer in cytochrome c oxidase from the cellular inside to the binuclear redox center (BNC) can occur through two distinct pathways, the D- and K-channels. For the protein to function as both a redox enzyme and a proton pump, proton transfer into the protein toward the BNC or toward a proton loading site (and ultimately through the membrane) must be highly regulated. The PR → F transition is the first step in a catalytic cycle that requires proton transfer from the bulk at the N-side to the BNC. Read More

    Major Reaction Coordinates Linking Transient Amyloid-β Oligomers to Fibrils Measured at Atomic Level.
    Biophys J 2017 Aug;113(4):805-816
    Department of Chemical Sciences, Tata Institute of Fundamental Research, Colaba, Mumbai, India; TIFR Centre for Interdisciplinary Sciences, Narsingi, Hyderabad, India. Electronic address:
    The structural underpinnings for the higher toxicity of the oligomeric intermediates of amyloidogenic peptides, compared to the mature fibrils, remain unknown at present. The transient nature and heterogeneity of the oligomers make it difficult to follow their structure. Here, using vibrational and solid-state nuclear magnetic resonance spectroscopy, and molecular dynamics simulations, we show that freely aggregating Aβ40 oligomers in physiological solutions have an intramolecular antiparallel configuration that is distinct from the intermolecular parallel β-sheet structure observed in mature fibrils. Read More

    Electrostatic Interactions at the Dimer Interface Stabilize the E. coli β Sliding Clamp.
    Biophys J 2017 Aug;113(4):794-804
    School of Molecular Sciences and Biodesign Institute, Arizona State University, Tempe, Arizona. Electronic address:
    Sliding clamps are ring-shaped oligomeric proteins that encircle DNA and associate with DNA polymerases for processive DNA replication. The dimeric Escherichia coli β-clamp is closed in solution but must adopt an open conformation to be assembled onto DNA by a clamp loader. To determine what factors contribute to the stability of the dimer interfaces in the closed conformation and how clamp dynamics contribute to formation of the open conformation, we identified conditions that destabilized the dimer and measured the effects of these conditions on clamp dynamics. Read More

    Bridging Microscopic and Macroscopic Mechanisms of p53-MDM2 Binding with Kinetic Network Models.
    Biophys J 2017 Aug;113(4):785-793
    Department of Chemistry, Temple University, Philadelphia, Pennsylvania. Electronic address:
    Under normal cellular conditions, the tumor suppressor protein p53 is kept at low levels in part due to ubiquitination by MDM2, a process initiated by binding of MDM2 to the intrinsically disordered transactivation domain (TAD) of p53. Many experimental and simulation studies suggest that disordered domains such as p53 TAD bind their targets nonspecifically before folding to a tightly associated conformation, but the microscopic details are unclear. Toward a detailed prediction of binding mechanisms, pathways, and rates, we have performed large-scale unbiased all-atom simulations of p53-MDM2 binding. Read More

    Rotation of Guanine Amino Groups in G-Quadruplexes: A Probe for Local Structure and Ligand Binding.
    Biophys J 2017 Aug;113(4):775-784
    Division of Physics and Applied Physics, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore, Singapore. Electronic address:
    Nucleic acids are dynamic molecules whose functions may depend on their conformational fluctuations and local motions. In particular, amino groups are dynamic components of nucleic acids that participate in the formation of various secondary structures such as G-quadruplexes. Here, we present a cost-efficient NMR method to quantify the rotational dynamics of guanine amino groups in G-quadruplex nucleic acids. Read More

    ParamAP: Standardized Parameterization of Sinoatrial Node Myocyte Action Potentials.
    Biophys J 2017 Aug;113(4):765-769
    Department of Physiology and Biophysics, University of Colorado-Anschutz Medical Campus, Aurora, Colorado. Electronic address:
    Sinoatrial node myocytes act as cardiac pacemaker cells by generating spontaneous action potentials (APs). Much information is encoded in sinoatrial AP waveforms, but both the analysis and the comparison of AP parameters between studies is hindered by the lack of standardized parameter definitions and the absence of automated analysis tools. Here we introduce ParamAP, a standalone cross-platform computational tool that uses a template-free detection algorithm to automatically identify and parameterize APs from text input files. Read More

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