Computational biophysics

  • Article
    | Open Access

    Dpr (Defective proboscis extension response) and DIP (Dpr Interacting Proteins) are immunoglobulin-like cell-cell adhesion proteins that form highly specific pairwise interactions, which control synaptic connectivity during Drosophila development. Here, the authors combine a computational approach with binding affinity measurements and find that DIP/Dpr binding specificity is controlled by negative constraints that interfere with non-cognate binding.

    • Alina P. Sergeeva
    • , Phinikoula S. Katsamba
    •  & Barry Honig
  • Article
    | Open Access

    Potassium (K+) channels, such as MthK, are essentional for many biological processes, but how lipid-protein interactions regulate ion permeation of K+ channels remained unclear. Here authors conducted molecular dynamics simulations of MthK and observed different ion permeation rates of MthK in membranes with different properties.

    • Ruo-Xu Gu
    •  & Bert L. de Groot
  • Article
    | Open Access

    Epithelial cell monolayers show remarkable displacement and velocity correlations over distances of ten or more cell sizes. Here the authors show that cell motility coupled to the collective elastic modes of the cell sheet is sufficient to produce characteristic swirl-like correlations.

    • Silke Henkes
    • , Kaja Kostanjevec
    •  & Eric Bertin
  • Article
    | Open Access

    Tripartite-motif containing (TRIM) proteins modulate cellular responses to viral infection. Here the authors use molecular dynamics simulations to demonstrate that TRIM5α uses a two-dimensional lattice hopping mechanism to aggregate on the HIV capsid surface and initiate lattice growth.

    • Alvin Yu
    • , Katarzyna A. Skorupka
    •  & Gregory A. Voth
  • Article
    | Open Access

    Although the permeation mechanisms for K+ and Na+ channels have been extensively studied, the ion permeation mechanism through Ca2+ channels was largely unknown. Here the authors develop a multisite Ca2+ model that can be used in the framework of classical MD simulations to study Ca2+ in a quantitative manner, and use it to investigate the ion permeation mechanism of the ryanodine receptor 1.

    • Aihua Zhang
    • , Hua Yu
    •  & Chen Song
  • Article
    | Open Access

    In the C. elegans zygote, (anterior) aPAR and (posterior) pPAR proteins are key to polarity maintenance, what factors determine the selection of the polarity axis remains unclear. Here authors formulate a reaction-diffusion model in realistic cell geometry and find that long-axis polarisation is promoted by cytosolic dephosphorylation at onset and its steady state determined by minimising the length of the aPAR-pPAR interface.

    • Raphaela Geßele
    • , Jacob Halatek
    •  & Erwin Frey
  • Article
    | Open Access

    Many RNA systems possess highly ordered 3-D structures that are essential to their function. Here the authors demonstrate that the long non-coding RNA Braveheart possesses a flexible but defined 3-D structure which is remodeled upon binding the protein CNBP.

    • Doo Nam Kim
    • , Bernhard C. Thiel
    •  & Karissa Y. Sanbonmatsu
  • Article
    | Open Access

    The design of protein assemblies is a major thrust for biomolecular engineering and nanobiotechnology. Here the authors demonstrate a general mechanism for designing allosteric macromolecular assemblies and showcase a proof of concept for engineered allosteric protein assembly.

    • Luis A. Campos
    • , Rajendra Sharma
    •  & Victor Muñoz
  • Article
    | Open Access

    Glioblastoma cells are known to be able to adapt easily to different environments. The authors study the dynamic adaptation of glioblastoma cells to the heterogenous brain tumor microenvironment, showing that tumor cells demonstrate varying plasticity of their transcriptomic profiles and an ability to survive new stimuli, in part, by propagating stochastic perturbations over their gene-regulatory network.

    • Orieta Celiku
    • , Mark R. Gilbert
    •  & Orit Lavi
  • Article
    | Open Access

    Natural creatures, from fish to snake and birds, combine neural control, sensory feedback and compliant mechanics to operate across uncertain environments. Here the authors present a versatile modeling approach to the dynamic simulation of their architectures based on the assembly of Cosserat rods.

    • Xiaotian Zhang
    • , Fan Kiat Chan
    •  & Mattia Gazzola
  • Article
    | Open Access

    Understanding vibrational energy transfer in macromolecules has been challenging to both theory and experiment. Here the authors use non-equilibrium molecular dynamics to reveal the relationship between heat transport in a model peptide, emergent nonlinearity, and the underlying free energy landscape.

    • Justin E. Elenewski
    • , Kirill A. Velizhanin
    •  & Michael Zwolak
  • Article
    | Open Access

    Besides mechanical forces, the mechanosensitive channel Piezo1 is activated by the small molecule Yoda1 through an unknown mechanism. Here, using molecular dynamics simulations, calcium imaging and electrophysiology, the authors identify an allosteric Yoda1 binding pocket located in the putative mechanosensory domain.

    • Wesley M. Botello-Smith
    • , Wenjuan Jiang
    •  & Yun Luo
  • Article
    | Open Access

    The calcium-activated chloride channel (CaCC) TMEM16A plays crucial roles in regulating neuronal excitability and muscle contraction. Here authors show that phosphatidylinositol (4,5)-bisphosphate (PIP2) regulates TMEM16A channel activation and desensitization via binding to a putative binding site.

    • Son C. Le
    • , Zhiguang Jia
    •  & Huanghe Yang
  • Article
    | Open Access

    Allosteric GPCR modulators can achieve exquisite subtype selectivity, but the underlying mechanism is unclear. Using molecular dynamics simulations, the authors here identify a previously undetected dynamic pocket in muscarinic GPCRs that is critical for subtype selectivity of allosteric modulators.

    • Scott A. Hollingsworth
    • , Brendan Kelly
    •  & Ron O. Dror
  • Article
    | Open Access

    The VASH2/SVBP heterodimer catalyzes the detyrosination of the α-tubulin C-terminus. Here the authors provide insights into the tubulin detyrosination mechanism by determining the crystal structures of VASH2/SVBP and VASH2/SVBP in complex with a tubulin tail peptide.

    • Chen Zhou
    • , Ling Yan
    •  & Zhu Liu
  • Article
    | Open Access

    Antibodies are generated through remote genomic interactions involving immunoglobulin variable (VH), diversity (DH) and joining (JH) gene segments. Here the authors develop a strategy to track VH-DHJH motion in B-lymphocytes and provide evidence that chromosome organisation near the sol-gel phase transition dictates the timing of genomic interactions to orchestrate gene expression and somatic recombination.

    • Nimish Khanna
    • , Yaojun Zhang
    •  & Cornelis Murre
  • Article
    | Open Access

    Chromatin is folded into Topologically Associating domains (TADs), with the organization and folding hierarchy of the TADs being highly dynamic. Here the authors develop a parsimonious randomly cross-linked (RCL) polymer model that maps high frequency encounters present in Hi-C data within and between TADs and reconstruct TADs across cell differentiation, revealing local chromatin re-organization.

    • O. Shukron
    • , V. Piras
    •  & D. Holcman
  • Article
    | Open Access

    RNA chaperones, such as the hepatitic C virus (HCV) core protein, are proteins that aid in the folding of nucleic acids. Here authors use single‐molecule spectroscopy and simulation to show that the HCV core protein acts as a flexible macromolecular counterion which facilitates nucleic acid folding.

    • Erik D. Holmstrom
    • , Zhaowei Liu
    •  & Benjamin Schuler
  • Article
    | Open Access

    Solutions of proteins and other molecules can host puzzling, solute-rich inclusions of mesoscopic dimensions. Here the authors report a mechanism by which mesoscopic clusters can nucleate and ripen, requiring that the solute form long-lived complexes, with implications for biologically and industrially relevant systems.

    • Ho Yin Chan
    •  & Vassiliy Lubchenko
  • Article
    | Open Access

    Bacterial chromosomes are tightly packed, limiting structural analysis by imaging techniques. Here, by quantitative time-lapse single-cell imaging of widened Escherichia coli cells, Wu and Japaridze et al. show that the chromosome exhibits a ring-like torus topology and a dynamic domain structure.

    • Fabai Wu
    • , Aleksandre Japaridze
    •  & Cees Dekker
  • Article
    | Open Access

    The bacterial protein Cnu together with the transcription repressor H-NS regulate expression of virulence factors in an osmo-sensitive manner. Here authors show that the structure of Cnu swells with decreasing ionic strength driving the oligomerization of H-NS and regulating osmo-sensory response.

    • Abhishek Narayan
    • , Soundhararajan Gopi
    •  & Athi N. Naganathan
  • Article
    | Open Access

    Ceramides are lipids that act directly on mitochondria to trigger apoptosis, but the underlying mechanism remains largely unclear. Here authors use a photoactivatable ceramide probe combined with a computation approach and functional studies to identify the voltage-dependent anion channel VDAC2 as a direct effector of ceramide-mediated cell death.

    • Shashank Dadsena
    • , Svenja Bockelmann
    •  & Joost C. M. Holthuis
  • Article
    | Open Access

    Cation-proton antiporters mediate selective ion exchange across cellular membranes to control pH, salt concentration and cell volume. Here the authors present a transition-path sampling method that overcomes the timescale gap between simulations (µs) and transport processes (s), which allows them to resolve the Na+ and H+ transport cycle of the Na+/H+ antiporter NhaP from Pyrococcus abyssi.

    • Kei-ichi Okazaki
    • , David Wöhlert
    •  & Gerhard Hummer
  • Article
    | Open Access

    During cell division, it is currently unclear how kinetochores transit from lateral microtubule attachment to durable association to dynamic microtubule plus ends. Here, using in vitro reconstitution and computer modeling, the authors provide biophysical mechanism for microtubule end-conversion driven by two kinetochore components, CENP-E and Ndc80 complex

    • Manas Chakraborty
    • , Ekaterina V. Tarasovetc
    •  & Ekaterina L. Grishchuk
  • Article
    | Open Access

    Bacteria grown on two carbon sources either consume both sources simultaneously or consume them sequentially. Here the authors use a metabolic network model of E. coli to show that optimal protein resource allocation and topological features of the network can explain the choice of carbon acquisition.

    • Xin Wang
    • , Kang Xia
    •  & Chao Tang
  • Article
    | Open Access

    It is unclear whether a constrictive force is exerted on the membrane from inside during bacterial cell division, or cell wall remodeling alone drives membrane constriction from outside. Here, the authors use simulations to explore different mechanisms for cell wall division, supporting that a constrictive force is required.

    • Lam T. Nguyen
    • , Catherine M. Oikonomou
    •  & Grant J. Jensen
  • Article
    | Open Access

    Understanding collective motions in a group of interacting animal is a challenge owing to the lack of control over, for example, real fish schools. Here, the authors study the aggregation of C. elegans at controllable conditions and reproduce the experimental observations using a minimal model.

    • Takuma Sugi
    • , Hiroshi Ito
    •  & Ken H. Nagai
  • Article
    | Open Access

    Allosteric interactions are an important contributor to the catalytic properties of enzyme. Here the authors demonstrate—using the prototypical protein kinase PKA—that the allosteric cooperativity underscoring substrate recognition and product release are directly linked to changes in conformational entropy.

    • Yingjie Wang
    • , Manu V.S.
    •  & Gianluigi Veglia
  • Article
    | Open Access

    Some retroviruses, including HIV, insert their DNA in a non-random manner in the host genome through a poorly understood selection mechanism. Here the authors develop a biophysical model of retroviral integration, identifying previously unnoticed universal principles that regulate this phenomenon.

    • D. Michieletto
    • , M. Lusic
    •  & E. Orlandini
  • Article
    | Open Access

    The detailed folding mechanisms of membrane proteins in their natural bilayer-like environments remains poorly understood due to the lack of tools for measuring stabilities and kinetics. Here, by simulating the folding of GlpG in a bilayer, the authors provide support for the helical-hairpin hypothesis and prompt a re-evaluation of a long-standing paradigm, the two-stage hypothesis.

    • Wei Lu
    • , Nicholas P. Schafer
    •  & Peter G. Wolynes
  • Article
    | Open Access

    Designing split protein approaches is time consuming and often results in high background activity due to spontaneous assembly. Here the authors present an automated approach which uses a split energy scoring function to identify optimal protein split sites and reduces spontaneous assembly.

    • Onur Dagliyan
    • , Andrey Krokhotin
    •  & Nikolay V. Dokholyan
  • Article
    | Open Access

    Processive chitinase is a linear molecular motor which moves on the surface of crystalline chitin. Here authors use single-molecule imaging, X-ray crystallography and simulations on chitinase A (SmChiA) and show that Brownian motion along the single chitin chain is rectified forward by substrate-assisted catalysis.

    • Akihiko Nakamura
    • , Kei-ichi Okazaki
    •  & Ryota Iino
  • Article
    | Open Access

    Forces are required for congression of chromosomes by microtubule spindles. Here, using super-resolution microscopy and computational modelling, the authors find that in addition to forces, torques caused by the microtubule motor protein kinesin-5 induce chirality and curves into the spindle.

    • Maja Novak
    • , Bruno Polak
    •  & Nenad Pavin
  • Article
    | Open Access

    Tools from statistical physics can be used to investigate a large variety of fields ranging from economics to biology. Here the authors first adapt density-functional theory to predict the distributions of crowds in new environments and then validate their approach using groups of fruit flies.

    • J. Felipe Méndez-Valderrama
    • , Yunus A. Kinkhabwala
    •  & T. A. Arias
  • Article
    | Open Access

    The human estrogen receptor alpha (hERα) is a hormone-responsive transcription factor. Here the authors combine small-angle X-ray scattering, hydroxyl radical protein footprinting and computational modeling and show that multidomain hERα adopts an L-shaped boot-like architecture revealing a cross-talk between its DNA-binding domain and Ligand-binding domain.

    • Wei Huang
    • , Yi Peng
    •  & Sichun Yang
  • Article
    | Open Access

    BK channels are regulated by membrane voltage and intracellular Ca2+ but the structural features that block the ion flow in the closed state remain unknown. Here authors use molecular dynamics simulation and show that a physical gate is not required; instead ion flow is regulated by hydrophobic dewetting due to changes in pore shape and surface hydrophobicity.

    • Zhiguang Jia
    • , Mahdieh Yazdani
    •  & Jianhan Chen
  • Article
    | Open Access

    The 3D organization of chromosomes within the nuclear space is important for biological functions. Here the authors model chromosomes as self-avoiding copolymers with distinct epigenetic states, and show that the features of experimentally generated contact maps can be reproduced and their dynamics predicted.

    • Guang Shi
    • , Lei Liu
    •  & D. Thirumalai
  • Article
    | Open Access

    Type II DNA topoisomerases (Top2s) direct the passage of one DNA duplex through another, which is important for resolving DNA entanglements. Here the authors combine X-ray crystallography and MD simulations and present the structure of the human Top2 DNA-gate in an open conformation and discuss mechanistic implications.

    • Shin-Fu Chen
    • , Nan-Lan Huang
    •  & Nei-Li Chan
  • Article
    | Open Access

    Single cell growth rate variability has been difficult to understand. Here, the authors apply a generalization of flux balance analysis to single cells based on maximum entropy modeling, and find that growth rate fluctuations of E. coli reflect metabolic flux variability and growth sub-optimality, in turn highlighting information costs for growth optimization.

    • Daniele De Martino
    • , Anna MC Andersson
    •  & Gašper Tkačik
  • Article
    | Open Access

    In Escherichia coli, outer membrane protein (OMP) cluster and form islands, but the origin and behaviour of those clusters remains poorly understood. Here authors use coarse grained molecular dynamics simulation and show that their mesoscale simulations recapitulate the restricted diffusion characteristics of OMPs.

    • Matthieu Chavent
    • , Anna L. Duncan
    •  & Mark S. P. Sansom
  • Article
    | Open Access

    Main-chain tracing remains a time-consuming task for medium resolution cryo-EM maps. Here the authors describe MAINMAST, a computational approach for building main-chain structure models of proteins from EM maps of 4-5 Å resolution that builds main-chain models of the protein by tracing local dense points in the density distribution.

    • Genki Terashi
    •  & Daisuke Kihara
  • Article
    | Open Access

    Biochemical processes require both high sensitivity and low fluctuation which is incompatible with the fluctuation dissipation theorem. Here Fei et al. model biochemical oscillators to show how free energy dissipation leads to both a suppression of phase fluctuation and an enhancement of phase sensitivity.

    • Chenyi Fei
    • , Yuansheng Cao
    •  & Yuhai Tu
  • Article
    | Open Access

    Membrane protein RodZ interacts with the actin-like protein MreB, which coordinates cell-wall insertion to maintain the typical rod-like shape of E. coli cells. Here, the authors provide evidence that RodZ modulates the biophysical properties of MreB and alters the spatial organization of cell-wall growth.

    • Alexandre Colavin
    • , Handuo Shi
    •  & Kerwyn Casey Huang
  • Article
    | Open Access

    The actomyosin cytoskeleton is known to spontaneously oscillate in many systems but the mechanism of this behavior is not clear. Here Qin et al. define a signaling network involving a ROCK-dependent self-activation loop and recruitment of myosin II to the cortex, followed by a local accumulation of myosin phosphatase that shuts off the signal.

    • Xiang Qin
    • , Edouard Hannezo
    •  & Xiaobo Wang