Computational biophysics

  • Article
    | Open Access

    The rational optimization of response times of protein conformational switches is a major challenge for biomolecular switch design. Here the authors present a generally applicable computational design strategy that in combination with biophysical experiments can improve response times using a Ca2+-sensor as an example.

    • Alex J. DeGrave
    • , Jeung-Hoi Ha
    •  & Lillian T. Chong
  • Article
    | Open Access

    NaK is a non-selective cation channel that conducts sodium (Na+) and potassium (K+) equally well. Here authors use ssNMR and MD simulations to show that the selectivity filter of NaK adopts two conformations in the absence of ions, one of which is preferred by Na+ and the other by K+.

    • Chaowei Shi
    • , Yao He
    •  & Han Sun
  • Article
    | Open Access

    Reptation theory has been widely adopted to describe the dynamics of entangled polymer solution, whereby a polymer follows the curvilinear Brownian motion along a tube. Here, the authors challenge this theory by showing long-time dynamics of semi-flexible polymers modulated by topological constraints.

    • Philipp Lang
    •  & Erwin Frey
  • Article
    | Open Access

    The transport dynamics of messenger ribonucleoproteins in neurons is crucial to our neuronal functions, but the detail remains elusive. Song et al. show that they are transported along the dendrites in alternating run and rest phases with their own random sojourn times, following an aging Lévy walk.

    • Minho S. Song
    • , Hyungseok C. Moon
    •  & Hye Yoon Park
  • Article
    | Open Access

    Neurotransmitter:sodium symporters (NSS) modulate the duration and magnitude of signaling via the sodium-coupled reuptake of neurotransmitters. Here the authors describe quantitative single molecule imaging of ligand-induced, functional dynamics of both intracellular and extracellular surfaces of LeuT, further defining the mechanism for NSS transport.

    • Daniel S. Terry
    • , Rachel A. Kolster
    •  & Scott C. Blanchard
  • Article
    | Open Access

    Traveling waves in the cell cortex can propagate much faster than actin waves, and the mechanism is unknown. Here the authors propose a mechanochemical feedback model for traveling waves that incorporates membrane shape changes and recruitment of F-BAR proteins that enables fast wave propagation.

    • Zhanghan Wu
    • , Maohan Su
    •  & Jian Liu
  • Article
    | Open Access

    An understanding of the dynamics of drug binding and unbinding processes is important for drug discovery. Here, the authors give insights into the binding mechanism of small drug-like molecules to human Hsp90 by combining thermodynamics and kinetics studies as well as molecular dynamics simulations.

    • M. Amaral
    • , D. B. Kokh
    •  & M. Frech
  • Article
    | Open Access

    The mechanics and structural transitions of DNA are important to many essential processes inside living cells. Here the authors combine theory and single-molecule experiments to show that intercalator binding stabilises a new structural state of DNA: hyperstretched DNA.

    • Koen Schakenraad
    • , Andreas S. Biebricher
    •  & Paul van der Schoot
  • Article
    | Open Access

    It is not known whether the shape of a cell can regulate cellular phenotype independently. Here, the authors show that culturing kidney podocytes or smooth muscle cells on 3-D biomimetic surfaces results in phenotypic changes and that cell shape is sensed by integrin β3 in a tension-independent manner.

    • Amit Ron
    • , Evren U. Azeloglu
    •  & Ravi Iyengar
  • Article
    | Open Access

    The process of HIV particle maturation involves complex molecular transitions. Here the authors combine NMR spectroscopy, cryo-EM, and molecular dynamics simulations to provide insight into the conformational equilibria in CA-SP1 assemblies relevant to HIV-1 maturation intermediates formation.

    • Mingzhang Wang
    • , Caitlin M. Quinn
    •  & Tatyana Polenova
  • Article
    | Open Access

    The effect of knots on protein stability and folding kinetics is not well understood. Here the authors combine optical tweezer experiments and calculations to experimentally determine the energy cost for knot formation, which indicates that knotted proteins evolved specific folding pathways because knot formation in unfolded chains is unfavorable.

    • Andrés Bustamante
    • , Juan Sotelo-Campos
    •  & Mauricio Báez
  • Article
    | Open Access

    While RNA folding is critical for its function, study of this process is challenging. Here, the authors combine nanopore single-molecule manipulation with theoretical analysis to follow the folding of an RNA pseudoknot, monitoring the intermediate states and the kinetics of their interconversion.

    • Xinyue Zhang
    • , Dong Zhang
    •  & Li-Qun Gu
  • Article
    | Open Access

    Binding and unbinding kinetics are important determinants of protein-protein or small molecule protein functional interactions that can guide drug development. Here the authors exploit the multi-ensemble Markov model framework to develop a computational approach that allows the estimation of binding kinetics reaching into the seconds timescale.

    • Fabian Paul
    • , Christoph Wehmeyer
    •  & Frank Noé
  • Article
    | Open Access

    The structure and mechanics of tissues is constantly perturbed by endogenous forces originated from cells. Here the authors show that 3D collagen gels, major components of connective tissues and extracellular matrix, are significantly and irreversibly remodelled by cellular traction forces and by macroscopic strains.

    • Jihan Kim
    • , Jingchen Feng
    •  & Bo Sun
  • Article
    | Open Access

    Biological polymeric matrices often use molecular anchors, such as antibodies, to trap nanoparticulates. Here, the authors find that anchor-matrix bonds that are weak and short-lived confer superior trapping potency, contrary to the prevailing belief that effective molecular anchors should form strong bonds to both the matrix and the nanoparticulates.

    • Jay Newby
    • , Jennifer L. Schiller
    •  & Samuel K. Lai
  • Article
    | Open Access

    Various stages of tissue morphogenesis involve the contraction of epithelial surfaces. Here, the authors identify the Rab GTPase Rab35 as an essential component of this contractile process, which functions as a membrane ratchet to ensure unidirectional movement of intercalating cells.

    • Cayla E. Jewett
    • , Timothy E. Vanderleest
    •  & J. Todd Blankenship
  • Article
    | Open Access

    Sensor histidine kinases (SHK) consist of sensor, linker and kinase modules and different models for SHK signal transduction have been proposed. Here the authors present nano- to millisecond time-resolved X-ray scattering measurements, which reveal a structural mechanism for kinase domain activation in SHK.

    • Oskar Berntsson
    • , Ralph P. Diensthuber
    •  & Sebastian Westenhoff
  • Article
    | Open Access

    The mechanisms that cause different cells to segregate into distinct tissues are unclear. Here the authors show in Xenopus that formation of a boundary between two tissues is driven by local tension along the interface rather than by global differences in adhesion or cortical contractility.

    • Laura Canty
    • , Eleyine Zarour
    •  & François Fagotto
  • Article
    | Open Access

    X-ray crystallography is the main method for protein structure determination. Here the authors combine solid-state NMR measurements and molecular dynamics simulations and show that crystal packing alters the thermodynamics and kinetics of local conformational exchange as well as overall rocking motion of protein molecules in the crystal lattice.

    • Vilius Kurauskas
    • , Sergei A. Izmailov
    •  & Paul Schanda
  • Article
    | Open Access

    Cells in the connective tissue are surrounded by a heterogeneous network of biopolymers. Here, the authors investigate how such heterogeneity affects cellular mechanosensing by simulating the deformation response of experimental and modelled biopolymer networks to locally applied forces.

    • Farzan Beroz
    • , Louise M. Jawerth
    •  & Ned S. Wingreen
  • Article
    | Open Access

    The emergence of novel catalytic functions in ancient proteins likely played a role in the evolution of modern enzymes. Here, the authors use protein sequences from Precambrian beta-lactamases and demonstrate that a single hydrophobic-to-ionizable amino acid mutation can lead to substantial Kemp eliminase activity.

    • Valeria A. Risso
    • , Sergio Martinez-Rodriguez
    •  & Jose M. Sanchez-Ruiz
  • Article
    | Open Access

    Circular dorsal ruffles (CDRs) are important for the vesicular uptake of extracellular matter, but the basis of their wave dynamics is not understood. Here, the authors propose and experimentally test a bistable reaction-diffusion system, which they show accounts for the typical CDR expansion and shrinkage and for aberrant formation of pinned waves and spirals.

    • Erik Bernitt
    • , Hans-Günther Döbereiner
    •  & Arik Yochelis
  • Article
    | Open Access

    Identifying pathways and transition states is critical to understanding chemical and biological reactions. Here, the authors introduce a capable computational approach using conformational space annealing to find multiple reaction pathways via global optimization of the Onsager-Machlup action.

    • Juyong Lee
    • , In-Ho Lee
    •  & Bernard R. Brooks
  • Article
    | Open Access

    Cell migration is sensitive to environmental stiffness, but how cells sense optimal stiffness is not known. Here the authors develop a model that predicts that the optimum can be shifted by altering the number of active molecular motors and clutches, and verify their model in two cell types.

    • Benjamin L. Bangasser
    • , Ghaidan A. Shamsan
    •  & David J. Odde
  • Article
    | Open Access

    Plastoquinone (PLQ) shuttles electrons between photosystem II (PSII) and cytochrome b6f. Here the authors perform molecular dynamics simulations and propose that PLQ enters the exchange cavity of PSII by a promiscuous diffusion mechanism whereby three different channels each act as entry and exit points.

    • Floris J. Van Eerden
    • , Manuel N. Melo
    •  & Siewert J. Marrink
  • Article
    | Open Access

    Studying the reactivity of ribozymes under extreme pressure could provide insights to optimize biocatalytic RNA design. Here, the authors show that at high pressure the transesterification step of the hairpin ribozyme self-cleavage reaction accelerates, while the overall process is slower.

    • Caroline Schuabb
    • , Narendra Kumar
    •  & Roland Winter
  • Article
    | Open Access

    Natural supplies of bryostatin, a compound in clinical trials for Alzheimer’s disease, cancer, and HIV, are scarce. Here, the authors perform molecular dynamics simulations to understand how bryostatin interacts with membrane-bound protein kinase C, offering insights for the design of bryostatin analogs.

    • Steven M. Ryckbosch
    • , Paul A. Wender
    •  & Vijay S. Pande
  • Article
    | Open Access

    The activity of G-protein-coupled receptors is regulated by their interaction with arrestins. Here the authors show that loops located on C-edge of arrestin-1 serve as a membrane anchor during the multi-step binding process that leads to a stable receptor–arrestin complex.

    • Ciara C M. Lally
    • , Brian Bauer
    •  & Martha E Sommer
  • Article
    | Open Access

    Tip-link filaments convey force to activate hair cells, important sensory receptors. Here the authors solve a partial structure of human protocadherin-15, a tip-link component with an unusual Ca2+–free linker that bends and is predicted to confer flexibility to this filament during inner-ear mechanotransduction.

    • Raul Araya-Secchi
    • , Brandon L. Neel
    •  & Marcos Sotomayor
  • Article
    | Open Access

    The translation of mRNA by the ribosome is governed by a series of large-scale conformational transitions. Here the authors use MD simulations to demonstrate how the rate of dissociation of elongation factor Tu affects the dynamics of tRNA accommodation and proofreading.

    • Jeffrey K. Noel
    •  & Paul C. Whitford
  • Article
    | Open Access

    The pH dependence of the activity of Escherichia colimain sodium-proton antiporter NhaA is still not fully understood. Here, the authors use continuous constant pH molecular dynamics simulations to identify NhaA proton carrier residues and elucidate its gating and ion transport processes.

    • Yandong Huang
    • , Wei Chen
    •  & Jana Shen
  • Article
    | Open Access

    Measuring the size distribution of nanomaterials in biological fluids is crucial to understand their properties in vivo. Here, the authors apply fluorescence recovery after photobleaching to measure protein aggregation in serum and to study permeability of biological membranes in mouse models.

    • Ranhua Xiong
    • , Roosmarijn E. Vandenbroucke
    •  & Kevin Braeckmans
  • Article
    | Open Access

    Over 5,000 km of open ocean separate central and eastern Pacific coral reefs. Here, the authors combine a biophysical dispersal model with genetic data to show that eastern Pacific coral populations have been isolated from western sources of larval recruitment since the 1997-98 El Niño-induced bleaching event.

    • S. Wood
    • , I. B. Baums
    •  & E. J. Hendy
  • Article
    | Open Access

    Conventional methods to quantify the migratory behaviour of cells assume that underlying parameters are constant. Mark et al.apply a superstatistical approach to extract time-dependent parameters of motile cells, and demonstrate an enhanced ability to distinguish between different migration strategies.

    • Claus Metzner
    • , Christoph Mark
    •  & Ben Fabry
  • Article
    | Open Access

    Epithelial sheet migration proceeds via a series of actomyosin contractions, called pulses, that are stabilized, or ratcheted. Here, Xie and Martin develop a computational framework to determine how pulses are coordinated, and show that ratcheting of pulses allows collective migration by preventing competition with neighbouring pulses.

    • Shicong Xie
    •  & Adam C. Martin
  • Article |

    Cold denaturation is the process by which globular proteins lose their structural integrity at sufficiently low temperatures. Here, the authors present an all-atom MD simulation of cold denaturation of the 16-mer hairpin peptide MrH1 using an explicit water model.

    • Changwon Yang
    • , Soonmin Jang
    •  & Youngshang Pak
  • Article
    | Open Access

    How microtubules are organized correctly in plant cells is not well understood. Ambroseet al. use 4D imaging and computer modelling to show that sharp cell edges induce microtubule depolymerization and that the microtubule-associated protein CLASP mitigates this process to modulate array organization.

    • Chris Ambrose
    • , Jun F. Allard
    •  & Geoffrey O. Wasteneys
  • Article |

    Seahorses evolved from pipefish, which have a remarkably different body shape. Here, by examining seahorse feeding behaviour and using a mathematical model, Van Wassenberghet al. demonstrate that the head, neck and trunk posture of the seahorse allows for the effective capture of their prey.

    • Sam Van Wassenbergh
    • , Gert Roos
    •  & Lara Ferry