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Articles below are published ahead of final publication in an issue. Please cite articles in the following format: authors, (year), title, journal, DOI.

August 9, 2022

New and Notable

New and Notable The soft breeze of the cation atmosphere around DNA

  • Fabien Ferrage,
  • Damien Laage
First published:August 09, 2022

August 4, 2022

Article

The role of ion-lipid interactions and lipid packing in ion-induced pores and transient defects caused by phenolic compounds

  • Sheikh I. Hossain,
  • Mathilda Seppelt,
  • Natalie Nguyen,
  • Chelsea Stokes,
  • Evelyne Deplazes
First published:August 04, 2022
The transient disruption of membranes for the passive permeation of ions or small molecules is a complex process relevant to understanding physiological processes and biotechnology applications. Phenolic compounds are widely studied for their antioxidant and antimicrobial properties, and many biological activities of phenolic compounds are based on their interactions with membranes. Ions are ubiquitous in cells and are known to alter the structure of phospholipid bilayers. Yet, ion-lipid interactions are usually ignored when studying the membrane-altering properties of phenolic compounds.

August 3, 2022

New and Notable

Membrane asymmetry enhances nanotube formation and limits pore resealing after electroporation

  • Sonali A. Gandhi,
  • Christopher V. Kelly
First published:August 03, 2022
Article

Molecular mechanisms of spontaneous curvature and softening in complex lipid bilayer mixtures

  • Henry J. Lessen,
  • Kayla C. Sapp,
  • Andrew H. Beaven,
  • Rana Ashkar,
  • Alexander J. Sodt
First published:August 03, 2022
Membrane reshaping is an essential biological process. The chemical composition of lipid membranes determines their mechanical properties, and thus the energetics of their shape. Hundreds of distinct lipid species make up native bilayers, and this diversity complicates efforts to uncover what compositional factors drive membrane stability in cells. Simplifying assumptions, therefore, are used to generate quantitative predictions of bilayer dynamics based on lipid composition. One assumption commonly used is that “per lipid” mechanical properties are both additive and constant — that they are an intrinsic property of lipids independent of the surrounding composition.
Article

Nucleation causes an actin network to fragment into multiple high-density domains

  • Aravind Chandrasekaran,
  • Edward Giniger,
  • Garegin A. Papoian
First published:August 03, 2022
Actin networks rely on nucleation mechanisms to generate new filaments because spontaneous nucleation is kinetically disfavored. Branching nucleation of actin filaments by Actin related protein (Arp2/3), in particular, is critical for actin self-organization. In this study, we use the simulation platform for active matter, MEDYAN, to generate 2000s long stochastic trajectories of actin networks, under varying Arp2/3 concentrations, in reaction volumes of biologically meaningful size (> 20μm3). We find that the dynamics of Arp2/3 increase the abundance of short filaments and increases network treadmilling rate.
Review

Single-Molecule Counting Applied to the Study of GPCR Oligomerization

  • J.N. Milstein,
  • D.F. Nino,
  • X. Zhou,
  • C.C. Gradinaru
First published:August 03, 2022
Single-molecule counting techniques enable a precise determination of the intracellular abundance and stoichiometry of proteins and macromolecular complexes. These details are often challenging to quantitatively assess yet are essential for our understanding of cellular function. Consider G protein-coupled receptors (GPCRs)—an expansive class of transmembrane signalling proteins that participate in many vital physiological functions making them a popular target for drug development. While early evidence for the role of oligomerization in receptor signalling came from ensemble biochemical and biophysical assays, innovations in single-molecule measurements are now driving a paradigm shift in our understanding of its relevance.
Article

Complex electrostatic effects on the selectivity of membrane-permeabilizing cyclic lipopeptides

  • Jessica Steigenberger,
  • Yentl Verleysen,
  • Niels Geudens,
  • Annemieke Madder,
  • José C. Martins,
  • Heiko Heerklotz
First published:August 03, 2022
Open Access
Cyclic lipopeptides (CLiPs) have many biological functions, including the selective permeabilization of target membranes, and technical and medical applications. We studied the anionic CLiP viscosin from Pseudomonas along with a neutral analog, pseudodesmin A, and the cationic viscosin-E2K to better understand electrostatic effects on target selectivity. Calcein leakage from liposomes of anionic phosphatidylglycerol (PG) and phosphatidylethanolamine (PE) is measured in comparison to net-neutral phosphatidylcholine by time-resolved fluorescence.
Article

Distribution of Cholesterol in Asymmetric Membranes Driven by Composition and Differential Stress

  • Malavika Varma,
  • Markus Deserno
First published:August 03, 2022
Many lipid membranes of eukaryotic cells are asymmetric, which means the two leaflets differ in at least one physical property, such as lipid composition or lateral stress. Maintaining this asymmetry is helped by the fact that ordinary phospholipids rarely transition between leaflets, but cholesterol is an exception: its flip-flop times are in the microsecond range, so that its distribution between leaflets is determined by a chemical equilibrium. In particular, preferential partitioning can draw cholesterol into a more saturated leaflet, and phospholipid number asymmetry can force it out of a compressed leaflet.
Article

Pulling, failing and adaptive mechanotransduction of macrophage filopodia

  • Rebecca Michiels,
  • Nicole Gensch,
  • Birgit Erhard,
  • Alexander Rohrbach
First published:August 03, 2022
Macrophages use filopodia to withdraw particles towards the cell body for phagocytosis. This can require substantial forces, which the cell generates after bio-mechanical stimuli are transmitted to the filopodium. Adaptation mechanisms to mechanical stimuli are essential for cells, but can a cell iteratively improve filopodia pulling? If so, the underlying mechanic adaptation principles organized on the protein level are unclear. Here we tackle this problem using optically trapped 1 μm beads, which we tracked interferometrically at 1 MHz during connection to the tips of dorsal filopodia of macrophages.
Article

Modelling intermediates of BamA folding an outer membrane protein

  • Katie M. Kuo,
  • David Ryoo,
  • Karl Lundquist,
  • James C. Gumbart
First published:August 03, 2022
BamA, the core component of the β-barrel assembly machinery (BAM) complex, is an integral outer membrane protein (OMP) in Gram-negative bacteria that catalyzes the folding and insertion of OMPs. A key feature of BamA relevant to its function is a lateral gate between its first and last β-strands. Opening of this lateral gate is one of the first steps in the asymmetric-hybrid-barrel model of BamA function. In this study, multiple hybrid-barrel folding intermediates of BamA and a substrate OMP, EspP, were constructed and simulated to better understand the model’s physical consequences.
Article

Effects of Clot Contraction on Clot Degradation: A Mathematical and Experimental Approach

  • Rebecca Risman,
  • Ahmed Abdelhamid,
  • John W. Weisel,
  • Brittany Bannish,
  • Valerie Tutwiler
First published:August 03, 2022
Open Access
Thrombosis, resulting in occlusive blood clots, blocks blood flow to downstream organs and causes life threatening conditions such as heart attacks and strokes. The administration of tissue plasminogen activator (t-PA) that drives the enzymatic degradation (fibrinolysis) of these blood clots is a treatment for thrombotic conditions, but the use of these therapeutics is often limited due to the time dependent nature of treatment and their limited success. We have shown that clot contraction, which is altered in prothrombotic conditions, influences the efficacy of fibrinolysis.
Article

Lipid redistribution in the highly curved footprint of Piezo1

  • Amanda Buyan,
  • D.W. Allender,
  • Ben Corry,
  • M. Schick
First published:August 03, 2022
We investigate the effects on the distribution of lipids in the plasma membrane that are caused by the insertion of a protein, Piezo1, that significantly distorts the membrane toward the cytosol. From coarse-grained molecular dynamics simulations, we find that the major effects occur in the outer, extracellular, leaflet. The mol fraction of cholesterol increases significantly in the curved region of the membrane close to Piezo1, while those of phosphatidylcholine and of sphingomyelin decrease. In the inner leaflet, mol fractions of cholesterol and of phosphatidylethanolamine decrease slightly as the protein is approached, while that of phosphatidylserine increases slightly.

August 2, 2022

Article

Mechanical regulation of the helicase activity of Zika virus NS3

  • Xiaocong Cao,
  • Kaixian Liu,
  • Shannon Yan,
  • Sai Li,
  • Yajuan Li,
  • Tengchuan Jin,
  • Shixin Liu
First published:August 02, 2022
Zika virus (ZIKV) is a positive-sense single-stranded RNA virus that infects humans and can cause birth defects and neurological disorders. Its non-structural protein 3 (NS3) contains a protease domain and a helicase domain, both of which play essential roles during the viral life cycle. However, it has been shown that ZIKV NS3 has an inherently weak helicase activity, making it unable to unwind long RNA duplexes alone. How this activity is stimulated to process the viral genome and whether the two domains of NS3 are functionally coupled remain unclear.
Article

Transmembrane peptide effects on bacterial membrane integrity and organization

  • Chloe J. Mitchell,
  • Tyler S. Johnson,
  • Charles M. Deber
First published:August 02, 2022
As the bacterial multidrug resistance crisis continues, membrane-active antimicrobial peptides (AMPs) have emerged as an alternate treatment to conventional antibiotics. In contrast to these AMPs, which largely function by a non-specific membrane disruption mechanism, we describe a series of transmembrane (TM) peptides that are designed to act as drug efflux inhibitors by aligning with and out-competing a conserved membrane-buried TM4-TM4 homodimerization motif within bacterial small multidrug resistance (SMR) proteins.
Article

Tomography of DNA tiles influences the kinetics of surface-mediated DNA self-assembly

  • Cuizheng Zhang,
  • Victoria E. Paluzzi,
  • Chengde Mao
First published:August 02, 2022
This manuscript studies the impact of extruding hairpins on two-dimensional self-assembly of DNA tiles on solid surface. Hairpins are commonly used as tomographic markers in DNA nanostructures for atomic force microscopy imaging. In this study, we have discovered that hairpins play a more active role. They modulate the adsorption of the DNA tiles onto the solid surface, thus changing the tile assembly kinetics on the solid surface. Based on this discovery, we were able to promote or slow down DNA self-assembly on the surface by changing the hairpin locations on the DNA tiles.

August 1, 2022

Article

Reduced Cardiac Muscle Power with low ATP simulating heart failure

  • Daniel A. Beard,
  • Bahador Marzban,
  • On Yeung Li,
  • Kenneth S. Campbell,
  • Paul M.L. Janssen,
  • Naomi C. Chesler,
  • Anthony J. Baker
First published:August 01, 2022
Open Access
For heart failure (HF) patients, myocardial ATP level can be reduced to one half of that observed in healthy controls. This marked reduction (from ≈ 8 mM in healthy controls to as low as 3-4 mM in HF) has been suggested to contribute to impaired myocardial contraction, and to the decreased pump function characteristic of heart failure. However, in vitro measures of maximum myofilament force generation, maximum shortening velocity, and the actomyosin ATPase activity show effective Km values for MgATP ranging from ≈ 10 μM -150 μM, well below the intracellular ATP level in heart failure.
Article

Aligned peptoid-based macrodiscs for structural studies of membrane proteins by oriented-sample NMR

  • Azamat R. Galiakhmetov,
  • Carolynn M. Davern,
  • Richard J.A. Esteves,
  • Emmanuel O. Awosanya,
  • Quibria A.E. Guthrie,
  • Caroline Proulx,
  • Alexander A. Nevzorov
First published:August 01, 2022
Development of a robust, uniform, and magnetically orientable lipid mimetic will undoubtedly advance solid-state NMR of macroscopically aligned membrane proteins. Here, we report on a novel lipid membrane mimetic based on peptoid belts. The peptoids, composed of 15 residues, were synthesized by alternating N-(2-phenethyl)glycine with N-(2-carboxyethyl)glycine residues at a 2:1 molar ratio. The chemically synthesized peptoids possess a much lower degree of polydispersity versus styrene-maleic acid polymers, thus yielding uniform discs.

July 20, 2022

Article

Measurement of the specific and non-specific binding energies of Mg2+ to RNA

  • A. Martinez-Monge,
  • Isabel Pastor,
  • Carlos Bustamante,
  • Maria Manosas,
  • Felix Ritort
First published:July 20, 2022
Determining the non-specific and specific electrostatic contributions of magnesium binding to RNA is a challenging problem. We introduce a single-molecule method based on measuring the folding energy of a native RNA in magnesium and at its equivalent sodium concentration. The latter is defined so that the folding energy in sodium equals the non-specific electrostatic contribution in magnesium. The sodium equivalent can be estimated according to the empirical 100/1 rule (1 M NaCl is equivalent to 10 mM MgCl2), which is a good approximation for most RNAs.

July 19, 2022

Article

Fluid-gel coexistence in lipid membranes under differential stress

  • Samuel L. Foley,
  • Amirali Hossein,
  • Markus Deserno
First published:July 19, 2022
A widely conserved property of many biological lipid bilayers is their asymmetry. In addition to having distinct compositions on its two sides, a membrane can also exhibit different tensions in its two leaflets, a state known as differential stress. Here, we examine how this stress can influence the phase behavior of the constituent lipid monolayers of a single-component membrane. For temperatures sufficiently close to, but still above, the main transition, molecular dynamics simulations show the emergence of finite gel domains within the compressed leaflet.
Article

Using sequence data to predict the self-assembly of supramolecular collagen structures

  • Anna M. Puszkarska,
  • Daan Frenkel,
  • Lucy J. Colwell,
  • Melinda J. Duer
First published:July 19, 2022
Open Access
Collagen fibrils are the major constituents of the extracellular matrix, which provides structural support to vertebrate connective tissues. It is widely assumed that the superstructure of collagen fibrils is encoded in the primary sequences of the molecular building blocks. However, the interplay between large-scale architecture and small-scale molecular interactions makes the ab initio prediction of collagen structure challenging. Here, we propose a model that allows us to predict the periodic structure of collagen fibers and the axial offset between the molecules, purely on the basis of simple predictive rules for the interaction between amino acid residues.
Article

Robustness in phenotypic plasticity and heterogeneity patterns enabled by EMT networks

  • Anish Hebbar,
  • Ankush Moger,
  • Kishore Hari,
  • Mohit Kumar Jolly
First published:July 19, 2022
Epithelial-Mesenchymal plasticity (EMP) is a key arm of cancer metastasis and is observed across many contexts. Cells undergoing EMP can reversibly switch between three classes of phenotypes: Epithelial (E), Mesenchymal (M), and Hybrid E/M. While a large number of multistable regulatory networks have been identified to be driving EMP in various contexts, the exact mechanisms and design principles that enable robustness in driving EMP across contexts are not yet fully understood. Here we investigated dynamic and structural robustness in EMP networks with regards to phenotypic heterogeneity and plasticity.

July 15, 2022

Article

Membrane fluidity, composition, and charge affect the activity and selectivity of the AMP ascaphin-8

  • Adriana Morales-Martínez,
  • Brandt Bertrand,
  • Juan M. Hernández-Meza,
  • Ramón Garduño-Juárez,
  • Jesús Silva-Sanchez,
  • Carlos Munoz-Garay
First published:July 15, 2022
Ascaphins are cationic antimicrobial peptides that have been shown to have potential in the treatment of infectious diseases caused by multidrug-resistant pathogens (MDR). However, to date, their principal molecular target and mechanism of action are unknown. Results from peptide prediction software and molecular dynamics simulations confirmed that ascaphin-8 is an alpha-helical peptide. For the first time, the peptide was described as membranotrophic using biophysical approaches including calcein liposome leakage, Laurdan general polarization, and dynamic light scattering.

July 14, 2022

Article

High hydrostatic pressure induces slow contraction in mouse cardiomyocytes

  • Yohei Yamaguchi,
  • Masayoshi Nishiyama,
  • Hiroaki Kai,
  • Toshiyuki Kaneko,
  • Keiko Kaihara,
  • Gentaro Iribe,
  • Akira Takai,
  • Keiji Naruse,
  • Masatoshi Morimatsu
First published:July 14, 2022
Open Access
Cardiomyocytes are contractile cells that regulate heart contraction. Ca2+ flux via Ca2+ channels activates actomyosin interactions, leading to cardiomyocyte contraction, which is modulated by physical factors (e.g., stretch, shear stress, and hydrostatic pressure). We evaluated the mechanism triggering slow contractions using a high-pressure microscope to characterize changes in cell morphology and intracellular Ca2+ concentration ([Ca2+]i) in mouse cardiomyocytes exposed to high hydrostatic pressures.
Article

Multisite phosphorylation and binding alter conformational dynamics of the 4E-BP2 protein

  • Spencer Smyth,
  • Zhenfu Zhang,
  • Alaji Bah,
  • Thomas E. Tsangaris,
  • Jennifer Dawson,
  • Julie D. Forman-Kay,
  • Claudiu C. Gradinaru
First published:July 14, 2022
Intrinsically disordered proteins (IDPs) play critical roles in regulatory protein interactions, but detailed structural/dynamics characterization of their ensembles remain challenging, both in isolation and when they form dynamic “fuzzy” complexes. Such is the case for mRNA cap-dependent translation initiation, which is regulated by the interaction of the predominantly folded eukaryotic initiation factor 4E (eIF4E) with the intrinsically disordered eIF4E binding proteins (4E-BPs) in a phosphorylation-dependent manner.
Article

Heterogeneous nanoscopic lipid diffusion in the live cell membrane and its dependency on cholesterol

  • Yu-Jo Chai,
  • Ching-Ya Cheng,
  • Yi-Hung Liao,
  • Chih-Hsiang Lin,
  • Chia-Lung Hsieh
First published:July 14, 2022
Open Access
Cholesterol plays a unique role in the regulation of membrane organization and dynamics by modulating the membrane phase transition at the nanoscale. Unfortunately, due to their small sizes and dynamic nature, the effects of cholesterol-mediated membrane nanodomains on membrane dynamics remain elusive. Here, using ultrahigh-speed single-molecule tracking with advanced optical microscope techniques, we investigate the diffusive motion of single phospholipids in the live cell plasma membrane at the nanoscale and its dependency on the cholesterol concentration.
Article

Effects of cholesterol on the structure and collapse of DPPC monolayers

  • Fazle R. Dayeen,
  • Bret A. Brandner,
  • Michael W. Martynowycz,
  • Kamil Kucuk,
  • Michael J. Foody,
  • Wei Bu,
  • Stephen B. Hall,
  • David Gidalevitz
First published:July 14, 2022
Cholesterol induces faster collapse by compressed films of pulmonary surfactant. Because collapse prevents films from reaching the high surface pressures achieved in the alveolus, most therapeutic surfactants remove or omit cholesterol. The studies here determined the structural changes by which cholesterol causes faster collapse by films of dipalmitoyl phosphatidylcholine, used as a simple model for the functional alveolar film. Measurements of isobaric collapse, with surface pressure held constant at 52 mN/m, showed that cholesterol had little effect until the mol fraction of cholesterol, Xchol, exceeded 0.20.

July 13, 2022

Article

A data-assimilation approach to predict population dynamics during epithelial-mesenchymal transition

  • Mario J. Mendez,
  • Matthew J. Hoffman,
  • Elizabeth M. Cherry,
  • Christopher A. Lemmon,
  • Seth H. Weinberg
First published:July 13, 2022
Epithelial-mesenchymal transition (EMT) is a biological process that plays a central role in embryonic development, tissue regeneration, and cancer metastasis. Transforming growth factor-β (TGFβ) is a potent inducer of this cellular transition, comprising transitions from an epithelial state to partial or hybrid EMT state(s), to a mesenchymal state. Recent experimental studies have shown that, within a population of epithelial cells, heterogeneous phenotypical profiles arise in response to different time- and TGFβ dose-dependent stimuli.

July 8, 2022

Article

Stability profile of the neuronal SNARE complex reflects its potency to drive fast membrane fusion

  • Shen Wang,
  • Cong Ma
First published:July 08, 2022
Soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) form the SNARE complex to mediate most fusion events of the secretory pathway. The neuronal SNARE complex is featured by its high stability and half-zippered conformation required for driving robust and fast synaptic exocytosis. However, these two features seem to be thermodynamically mutually exclusive. In this study, we have employed temperature-dependent disassociation assays and single-molecule Förster resonance energy transfer (FRET) experiments to analyze the stability and conformation of the neuronal SNARE complex.
Article

Interrogating the substrate specificity landscape of UvrC reveals novel insights into its non-canonical function

  • Manoj Thakur,
  • Rishikesh S. Parulekar,
  • Sagar S. Barale,
  • Kailas D. Sonawane,
  • Kalappa Muniyappa
First published:July 08, 2022
Although it is relatively unexplored, accumulating data highlight the importance of tripartite crosstalk between nucleotide excision repair (NER), DNA replication, and recombination in the maintenance of genome stability; however, elucidating the underlying mechanisms remains challenging. While Escherichia coli uvrA and uvrB can fully complement polAΔ cells in DNA replication, uvrC attenuates this alternative DNA replication pathway, but the exact mechanism by which uvrC suppresses DNA replication is unknown.
Article

Repetitive DNA symmetry elements negatively regulate gene expression in embryonic stem cells

  • Meir Mellul,
  • Shlomtzion Lahav,
  • Masahiko Imashimizu,
  • Yuji Tokunaga,
  • David B. Lukatsky,
  • Oren Ram
First published:July 08, 2022
Transcription factor (TF) binding to genomic DNA elements constitutes one of the key mechanisms that regulates gene expression program in cells. Both consensus and nonconsensus DNA sequence elements influence the recognition specificity of TFs. Based on the analysis of experimentally determined c-Myc binding preferences to genomic DNA, here we statistically predict that certain repetitive, nonconsensus DNA symmetry elements can relatively reduce TF-DNA binding preferences. This is in contrast to a different set of repetitive, nonconsensus symmetry elements that can increase the strength of TF-DNA binding.

July 7, 2022

New and Notable

Using balloons and rubber bands to learn about inter-cellular bridges

  • Stefano Di Talia
First published:July 07, 2022
The proper functioning of multicellular systems often requires a high degree of coordination among the behaviors of individual cells. Such coordination arises from the ability of cells to communicate with each other. This communication is mediated by both mechanical and biochemical signals (1–3). Among the biochemical signals that can drive this coordination, extracellular ligands are often implicated as mechanisms for long-range coordination (4). However, in several biological contexts, most notably gametogenesis, cell-cell communication is ensured by the fact that cells remain physically connected via inter-cellular bridges (ICBs).
Article

A conserved Trp residue in HwBR contributes to its unique tolerance toward acidic environments

  • Cheng-Han Yu,
  • Hsiang-Yu Wu,
  • Hong-Syuan Lin,
  • Chii-Shen Yang
First published:July 07, 2022
Bacteriorhodopsin (BR) is a light-driven outward proton pump found mainly in halophilic archaea. A BR from an archaeon Haloquadratum walsbyi (HwBR) was found to pump protons under more acidic conditions compared with most known BR proteins. The atomic structural study on HwBR unveiled that a pair of hydrogen bonds between the BC and FG loop in its periplasmic region may be a factor in such improved pumping capability. Here, we further investigated the retinal-binding pocket of HwBR and found that Trp94 contributes to the higher acid tolerance.

July 6, 2022

Article

Mechanisms of isoform-specific residue influence on GTP-bound HRas, KRas, and NRas

  • Alicia Y. Volmar,
  • Hugo Guterres,
  • Hao Zhou,
  • Derion Reid,
  • Spiro Pavlopoulos,
  • Lee Makowski,
  • Carla Mattos
First published:July 06, 2022
HRas, KRas, and NRas are GTPases with a common set of effectors that control many cell-signaling pathways, including proliferation through Raf kinase. Their G-domains are nearly identical in sequence, with a few isoform-specific residues that have an effect on dynamics and biochemical properties. Here, we use accelerated molecular dynamics (aMD) simulations consistent with solution x-ray scattering experiments to elucidate mechanisms through which isoform-specific residues associated with each Ras isoform affects functionally important regions connected to the active site.

July 3, 2022

Biophysical Perspective

Crystallographic legacy of Ned Seeman

  • Helen M. Berman,
  • George DeTitta
First published:July 03, 2022
We trace the career path of Nadrian Seeman, the inventor of DNA nanotechnology. The influence of his early training in crystallography and how this led to his success in creating self-assembled crystals are highlighted.

June 30, 2022

Article

Mechanics of stabilized intercellular bridges

  • Jaspreet Singh,
  • Jasmin Imran Alsous,
  • Krishna Garikipati,
  • Stanislav Y. Shvartsman
First published:June 30, 2022
Numerous engineered and natural systems form through reinforcement and stabilization of a deformed configuration that was generated by a transient force. An important class of such structures arises during gametogenesis, when a dividing cell undergoes incomplete cytokinesis, giving rise to daughter cells that remain connected through a stabilized intercellular bridge (ICB). ICBs can form through arrest of the contractile cytokinetic furrow and its subsequent stabilization. Despite knowledge of the molecular components, the mechanics underlying robust ICB assembly and the interplay between ring contractility and stiffening are poorly understood.
Article

Exploring CRD mobility during RAS/RAF engagement at the membrane

  • Kien Nguyen,
  • Cesar A. López,
  • Chris Neale,
  • Que N. Van,
  • Timothy S. Carpenter,
  • Francesco Di Natale,
  • Timothy Travers,
  • Timothy H. Tran,
  • Albert H. Chan,
  • Harsh Bhatia,
  • Peter H. Frank,
  • Marco Tonelli,
  • Xiaohua Zhang,
  • Gulcin Gulten,
  • Tyler Reddy,
  • Violetta Burns,
  • Tomas Oppelstrup,
  • Nick Hengartner,
  • Dhirendra K. Simanshu,
  • Peer-Timo Bremer,
  • De Chen,
  • James N. Glosli,
  • Rebika Shrestha,
  • Thomas Turbyville,
  • Frederick H. Streitz,
  • Dwight V. Nissley,
  • Helgi I. Ingólfsson,
  • Andrew G. Stephen,
  • Felice C. Lightstone,
  • Sandrasegaram Gnanakaran
First published:June 30, 2022
During the activation of mitogen-activated protein kinase (MAPK) signaling, the RAS-binding domain (RBD) and cysteine-rich domain (CRD) of RAF bind to active RAS at the plasma membrane. The orientation of RAS at the membrane may be critical for formation of the RAS-RBDCRD complex and subsequent signaling. To explore how RAS membrane orientation relates to the protein dynamics within the RAS-RBDCRD complex, we perform multiscale coarse-grained and all-atom molecular dynamics (MD) simulations of KRAS4b bound to the RBD and CRD domains of RAF-1, both in solution and anchored to a model plasma membrane.
Article

Labeling of a mutant estrogen receptor with an Affimer in a breast cancer cell line

  • Pin Ren,
  • Christian Tiede,
  • Sean W. Fanning,
  • Thomas Adams,
  • Valerie Speirs,
  • Erik R. Nelson,
  • Changfeng Cheng,
  • Terry W. Moore,
  • Geoffrey L. Greene,
  • Darren Tomlinson,
  • Paul R. Selvin
First published:June 30, 2022
Mutations of the intracellular estrogen receptor alpha (ERα) is implicated in 70% of breast cancers. Therefore, it is of considerable interest to image various mutants (L536S, Y537S, D538G) in living cancer cell lines, particularly as a function of various anticancer drugs. We therefore developed a small (13 kDa) Affimer, which, after fluorescent labeling, is able to efficiently label ERα by traveling through temporary pores in the cell membrane, created by the toxin streptolysin O. The Affimer, selected by a phage display, predominantly labels the Y537S mutant and can tell the difference between L536S and D538G mutants.

June 27, 2022

Article

Effects of polycationic drug carriers on the electromechanical and swelling properties of cartilage

  • Matthew R. Warren,
  • Armin Vedadghavami,
  • Sanjana Bhagavatula,
  • Ambika G. Bajpayee
First published:June 27, 2022
Cationic nanocarriers offer a promising solution to challenges in delivering drugs to negatively charged connective tissues, such as to articular cartilage for the treatment of osteoarthritis (OA). However, little is known about the effects that cationic macromolecules may have on the mechanical properties of cartilage at high interstitial concentrations. We utilized arginine-rich cationic peptide carriers (CPCs) with varying net charge (from +8 to +20) to investigate the biophysical mechanisms of nanocarrier-induced alterations to cartilage biomechanical properties.

June 25, 2022

Article

Diffusion NMR-based comparison of electrostatic influences of DNA on various monovalent cations

  • Binhan Yu,
  • Karina G. Bien,
  • Tianzhi Wang,
  • Junji Iwahara
First published:June 25, 2022
Counterions are important constituents for the structure and function of nucleic acids. Using 7Li and 133Cs nuclear magnetic resonance (NMR) spectroscopy, we investigated how ionic radii affect the behavior of counterions around DNA through diffusion measurements of Li+ and Cs+ ions around a 15-bp DNA duplex. Together with our previous data on 23Na+ and 15NH4+ ions around the same DNA under the same conditions, we were able to compare the dynamics of four different monovalent ions around DNA. From the apparent diffusion coefficients at varied concentrations of DNA, we determined the diffusion coefficients of these cations inside and outside the ion atmosphere around DNA (Db and Df, respectively).

June 15, 2022

Review

Ned Seeman and the prediction of amino acid-basepair motifs mediating protein-nucleic acid recognition

  • Martin Egli,
  • Shuguang Zhang
First published:June 15, 2022
Fifty years ago, the first atomic-resolution structure of a nucleic acid double helix, the mini-duplex (ApU)2, revealed details of basepair geometry, stacking, sugar conformation, and backbone torsion angles, thereby superseding earlier models based on x-ray fiber diffraction, including the original DNA double helix proposed by Watson and Crick. Just 3 years later, in 1976, Ned Seeman, John Rosenberg, and Alex Rich leapt from their structures of mini-duplexes and H-bonding motifs between bases in small-molecule structures and transfer RNA to predicting how proteins could sequence specifically recognize double helix nucleic acids.

June 5, 2022

Article

GM1 asymmetry in the membrane stabilizes pores

  • Mina Aleksanyan,
  • Rafael B. Lira,
  • Jan Steinkühler,
  • Rumiana Dimova
First published:June 05, 2022
Cell membranes are highly asymmetric and their stability against poration is crucial for survival. We investigated the influence of membrane asymmetry on electroporation of giant unilamellar vesicles with membranes doped with GM1, a ganglioside asymmetrically enriched in the outer leaflet of neuronal cell membranes. Compared with symmetric membranes, the lifetimes of micronsized pores are about an order of magnitude longer suggesting that pores are stabilized by GM1. Internal membrane nanotubes caused by the GM1 asymmetry, obstruct and additionally slow down pore closure, effectively reducing pore edge tension and leading to leaky membranes.

May 30, 2022

Article

Computational compensatory mutation discovery approach: Predicting a PARP1 variant rescue mutation

  • Krithika Ravishankar,
  • Xianli Jiang,
  • Emmett M. Leddin,
  • Faruck Morcos,
  • G. Andrés Cisneros
First published:May 30, 2022
The prediction of protein mutations that affect function may be exploited for multiple uses. In the context of disease variants, the prediction of compensatory mutations that reestablish functional phenotypes could aid in the development of genetic therapies. In this work, we present an integrated approach that combines coevolutionary analysis and molecular dynamics (MD) simulations to discover functional compensatory mutations. This approach is employed to investigate possible rescue mutations of a poly(ADP-ribose) polymerase 1 (PARP1) variant, PARP1 V762A, associated with lung cancer and follicular lymphoma.

May 25, 2022

Article

Crowding-induced membrane remodeling: Interplay of membrane tension, polymer density, architecture

  • Sreeja Kutti Kandy,
  • Ravi Radhakrishnan
First published:May 25, 2022
The plasma membrane hosts a wide range of biomolecules, mainly proteins and carbohydrates, that mediate cellular interactions with its environment. The crowding of such biomolecules regulates cellular morphologies and cellular trafficking. Recent discoveries have shown that the structure and density of cell surface polymers and hence the signaling machinery change with the state of the cell, especially in cancer progression. The alterations in membrane-attached glycocalyx and glycosylation of proteins and lipids are common features of cancer cells.
Article

Structural and biophysical properties of farnesylated KRas interacting with the chaperone SmgGDS-558

  • Dennis J. Michalak,
  • Bethany Unger,
  • Ellen Lorimer,
  • Alexander Grishaev,
  • Carol L. Williams,
  • Frank Heinrich,
  • Mathias Lösche
First published:May 25, 2022
KRas is a small GTPase and membrane-bound signaling protein. Newly synthesized KRas is post-translationally modified with a membrane-anchoring prenyl group. KRas chaperones are therapeutic targets in cancer due to their participation in trafficking oncogenic KRas to membranes. SmgGDS splice variants are chaperones for small GTPases with basic residues in their hypervariable domain (HVR), including KRas. SmgGDS-607 escorts pre-prenylated small GTPases, while SmgGDS-558 escorts prenylated small GTPases.

May 13, 2022

Article

Optimal pathways control fixation of multiple mutations during cancer initiation

  • Hamid Teimouri,
  • Cade Spaulding,
  • Anatoly B. Kolomeisky
First published:May 13, 2022
Cancer starts after initially healthy tissue cells accumulate several specific mutations or other genetic alterations. The dynamics of tumor formation is a very complex phenomenon due to multiple involved biochemical and biophysical processes. It leads to a very large number of possible pathways on the road to final fixation of all mutations that marks the beginning of the cancer, complicating the understanding of microscopic mechanisms of tumor formation. We present a new theoretical framework of analyzing the cancer initiation dynamics by exploring the properties of effective free-energy landscape of the process.

May 10, 2022

Article

Biophysical insights into OR2T7: Investigation of a potential prognostic marker for glioblastoma

  • Amanda K. Sharp,
  • David Newman,
  • Gianna Libonate,
  • Mary Borns-Stern,
  • David R. Bevan,
  • Anne M. Brown,
  • Ramu Anandakrishnan
First published:May 10, 2022
Glioblastoma multiforme (GBM) is the most aggressive and prevalent form of brain cancer, with an expected survival of 12–15 months following diagnosis. GBM affects the glial cells of the central nervous system, which impairs regular brain function including memory, hearing, and vision. GBM has virtually no long-term survival even with treatment, requiring novel strategies to understand disease progression. Here, we identified a somatic mutation in OR2T7, a G-protein-coupled receptor (GPCR), that correlates with reduced progression-free survival for glioblastoma (log rank p-value = 0.05), suggesting a possible role in tumor progression.

May 2, 2022

Review

Cancer as a biophysical disease: Targeting the mechanical-adaptability program

  • Ly T.S. Nguyen,
  • Mark Allan C. Jacob,
  • Eleana Parajón,
  • Douglas N. Robinson
First published:May 02, 2022
With the number of cancer cases projected to significantly increase over time, researchers are currently exploring “nontraditional” research fields in the pursuit of novel therapeutics. One emerging area that is steadily gathering interest revolves around cellular mechanical machinery. When looking broadly at the physical properties of cancer, it has been debated whether a cancer could be defined as either stiffer or softer across cancer types. With numerous articles supporting both sides, the evidence instead suggests that cancer is not particularly regimented.
Article

Adhesion strength between cells regulate nonmonotonic growth by a biomechanical feedback mechanism

  • Abdul N. Malmi-Kakkada,
  • Sumit Sinha,
  • Xin Li,
  • D. Thirumalai
First published:May 02, 2022
We determine how intercellular interactions and mechanical pressure experienced by single cells regulate cell proliferation using a minimal computational model for three-dimensional multicellular spheroid (MCS) growth. We discover that emergent spatial variations in the cell division rate, depending on the location of the cells either at the core or periphery within the MCS, is regulated by intercellular adhesion strength (fad). Varying fad results in nonmonotonic proliferation of cells in the MCS.

April 24, 2022

Article

Left versus right: Exploring the effects of chiral threading intercalators using optical tweezers

  • Adam A. Jabak,
  • Nicholas Bryden,
  • Fredrik Westerlund,
  • Per Lincoln,
  • Micah J. McCauley,
  • Ioulia Rouzina,
  • Mark C. Williams,
  • Thayaparan Paramanathan
First published:April 24, 2022
Small-molecule DNA-binding drugs have shown promising results in clinical use against many types of cancer. Understanding the molecular mechanisms of DNA binding for such small molecules can be critical in advancing future drug designs. We have been exploring the interactions of ruthenium-based small molecules and their DNA-binding properties that are highly relevant in the development of novel metal-based drugs. Previously we have studied the effects of the right-handed binuclear ruthenium threading intercalator ΔΔ-[μ-bidppz(phen)4Ru2]4+, or ΔΔ-P for short, which showed extremely slow kinetics and high-affinity binding to DNA.

April 22, 2022

Article

Millisecond molecular dynamics simulations of KRas-dimer formation and interfaces

  • Van A. Ngo,
  • Angel E. Garcia
First published:April 22, 2022
Ras dimers have been proposed as building blocks for initiating the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) cellular signaling pathway. To better examine the structure of possible dimer interfaces, the dynamics of Ras dimerization, and its potential signaling consequences, we performed molecular dynamics simulations totaling 1 ms of sampling, using an all-atom model of two full-length, farnesylated, guanosine triphosphate (GTP)-bound, wild-type KRas4b proteins diffusing on 29%POPS (1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-L-serine)-mixed POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine) membranes.

April 21, 2022

Article

Conformational transitions in BTG1 antiproliferative protein and their modulation by disease mutants

  • Ekaterina Kots,
  • Coraline Mlynarczyk,
  • Ari Melnick,
  • George Khelashvili
First published:April 21, 2022
B cell translocation gene 1 (BTG1) protein belongs to the BTG/transducer of ERBB2 (TOB) family of antiproliferative proteins whose members regulate various key cellular processes such as cell cycle progression, apoptosis, and differentiation. Somatic missense mutations in BTG1 are found in ∼70% of a particularly malignant and disseminated subtype of diffuse large B cell lymphoma (DLBCL). Antiproliferative activity of BTG1 has been linked to its ability to associate with transcriptional cofactors and various enzymes.
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