Computational biophysics

  • Article
    | Open Access

    A long puzzle in snake’s locomotion, sidewinding allows them to travel at an angle and reorient in some environments without loss of speed. Here, authors provide a mathematical argument to the evolution of sidewinding gaits and reinforce an analogy between limbless terrestrial locomotion and optics.

    • Xiaotian Zhang
    • , Noel Naughton
    •  & Mattia Gazzola
  • Article
    | Open Access

    Gene-regulatory networks are thought to be complex, and yet perturbation of just a few transcription factors (TFs) can have major consequences. Here the authors apply DNA polymer modelling and simulations to predict how 3D genome structure and TF-DNA interactions can give rise to transcriptional regulation operating over broad genomic regions, where small perturbations can have long-reaching effects.

    • C. A. Brackley
    • , N. Gilbert
    •  & D. Marenduzzo
  • Article
    | Open Access

    The mechanisms involved in SLC4-mediated ion transport are still under debate. Here, the authors present a cryoEM structure of the Sodium-driven Chloride/Bicarbonate Exchanger NDCBE, which - together with computational modeling and mutagenesis - reveals molecular determinants of ion transport by SLC4.

    • Weiguang Wang
    • , Kirill Tsirulnikov
    •  & Ira Kurtz
  • Article
    | Open Access

    The SARS-CoV-2 Spike protein is essential for viral infectivity and binds to the host receptor ACE2. Here, the authors present MD simulations of the Spike protein and its variants of concern and observe that the Spike protein is destabilised by moderate static electric fields, and undergoes field-induced conformational changes that hinder binding to ACE2.

    • Claudia R. Arbeitman
    • , Pablo Rojas
    •  & Martin E. Garcia
  • Article
    | Open Access

    The intrinsic disorder of histone tails poses challenges in their characterization. Here the authors apply extensive molecular dynamics simulations of the full nucleosome to show reversible binding to DNA with specific binding modes of different types of histone tails, where charge-altering modifications suppress tail-DNA interactions and may boost interactions between nucleosomes and nucleosome-binding proteins.

    • Yunhui Peng
    • , Shuxiang Li
    •  & Anna R. Panchenko
  • Article
    | Open Access

    The analysis of NMR spectra of complex biochemical samples with respect to individual resonances is challenging but critically important. Here, the authors present a deep learning-based method that accelerates this process also for crowded NMR data that are non-trivial to analyze, even by expert NMR spectroscopists.

    • Da-Wei Li
    • , Alexandar L. Hansen
    •  & Rafael Brüschweiler
  • Article
    | Open Access

    DNA probes used in next generation sequencing (NGS) have variable hybridisation kinetics, resulting in non-uniform coverage. Here, the authors develop a deep learning model to predict NGS depth using DNA probe sequences and apply to human and non-human sequencing panels.

    • Jinny X. Zhang
    • , Boyan Yordanov
    •  & David Yu Zhang
  • Article
    | Open Access

    High-speed atomic force microscopy height spectroscopy and single channel electrophysiology recordings are used to correlate conformational and functional dynamics of the model membrane protein, outer membrane protein G (OmpG). These techniques show that both states coexist and rapidly interchange in all conditions supported by molecular dynamics simulations.

    • Raghavendar Reddy Sanganna Gari
    • , Joel José Montalvo‐Acosta
    •  & Simon Scheuring
  • Article
    | Open Access

    The cryo-EM structure of pentameric green-light absorbing proteorhodopsin together with molecular dynamics simulations and functional studies provides insights into the proton translocation pathway and oligomerization, and a protonation-dependent mechanism for intracellular half channel hydration.

    • Stephan Hirschi
    • , David Kalbermatter
    •  & Dimitrios Fotiadis
  • Article
    | Open Access

    The intracellular compartment is a crowded environment. Here, the authors use molecular dynamics (MD) simulations to assess inhibitor binding to c-Src kinase and show how ligand binding pathways differ in crowded and dilute protein solutions, highlighting the role of c-Src Tyr82 sidechain.

    • Kento Kasahara
    • , Suyong Re
    •  & Yuji Sugita
  • Article
    | Open Access

    The glucagon-like peptide-1 (GLP-1) receptor is a key regulator of glucose homeostasis and a drug target for type 2 diabetes but available GLP-1R agonists are suboptimal due to several side-effects. Here authors report the cryo-EM structure of GLP-1R bound to an ago-allosteric modulator in complex with heterotrimeric Gs which offers insights into the molecular details of ago-allosterism.

    • Zhaotong Cong
    • , Li-Nan Chen
    •  & Ming-Wei Wang
  • Article
    | Open Access

    Vibrational energy transfer (VET) is essential for protein function as it is responsible for efficient energy dissipation in reaction sites and is linked to pathways of allosteric communication. Here authors equipped a tryptophan zipper with a VET injector and a VET sensor for femtosecond pump probe experiments to map the VET.

    • Erhan Deniz
    • , Luis Valiño-Borau
    •  & Jens Bredenbeck
  • Article
    | Open Access

    Resolving nucleosomes with chemical accuracy inside sub-Mb chromatin provides molecular insight into the modulation of chromatin structure and its liquid–liquid phase separation (LLPS). By developing a multiscale chromatin model, the authors find that DNA breathing enhances the valency, heterogeneity, and dynamics of nucleosomes, promoting disordered folding and LLPS.

    • Stephen E. Farr
    • , Esmae J. Woods
    •  & Rosana Collepardo-Guevara
  • Article
    | Open Access

    Molecular dynamics (MD) techniques enable atomic-level observations, but simulations of “slow” biomolecular processes are challenging because of current computer speed limitations. Here, the authors develop a method to accelerate MD simulations by high-frequency ultrasound perturbation and reveal binding events between the protein CDK2 and its small-molecule inhibitors.

    • Mitsugu Araki
    • , Shigeyuki Matsumoto
    •  & Yasushi Okuno
  • Article
    | Open Access

    The adult ocellated lizard skin colour pattern is effectively generated by a stochastic cellular automaton (CA) of skin scales. Here authors use reaction diffusion (RD) numerical simulations in 3D on realistic lizard skin geometries and demonstrate that skin thickness variation on its own is sufficient to cause scale-by-scale coloration and CA dynamics during RD patterning.

    • Anamarija Fofonjka
    •  & Michel C. Milinkovitch
  • Article
    | Open Access

    Nucleosomes tightly wrap ~147 DNA base pairs around an octamer of histone proteins, but how nucleosome structural dynamics affect genome functioning is not completely clear. Here authors employ all-atom molecular dynamics simulations of nucleosome core particles and observe that octamer dynamics and plasticity enable DNA unwrapping and sliding.

    • Grigoriy A. Armeev
    • , Anastasiia S. Kniazeva
    •  & Alexey K. Shaytan
  • Article
    | Open Access

    Intrinsically disordered FG-Nups line the Nuclear Pore Complex (NPC) lumen and form a selective barrier where transport of most proteins is inhibited, whereas specific transporter proteins are able to pass. Here, the authors reconstitute the selective behaviour of the NPC by introducing a rationally designed artificial FG-Nup that demonstrates that no specific spacer sequence nor a spatial segregation of different FG-motif types are needed to create selective NPCs.

    • Alessio Fragasso
    • , Hendrik W. de Vries
    •  & Cees Dekker
  • Article
    | Open Access

    TEM-1 β-lactamase evolved from ancestral enzymes that degraded a variety of β-lactam antibiotics with moderate efficiency and degrades β-lactam antibiotics with a strong preference for penicillins. Here authors developed a computational approach to rationally mold a protein flexibility profile on the basis of a hinge-shift mechanism and show a putative Precambrian β-lactamase that mimics the modern TEM-1 β-lactamase with only 21 amino acid replacements.

    • Tushar Modi
    • , Valeria A. Risso
    •  & S. Banu Ozkan
  • Article
    | Open Access

    Buried charged networks in proteins are often important for their biological functionality and are believed to destabilise the protein fold. Here, the authors combine computational design, MD simulations, biophysical experiments, NMR and X-ray crystallography to design and characterise artificial 4α-helical proteins with buried charged elements. They analyse their conformational landscapes and observe that the ion-pairs are stabilised by amphiphilic residues that electrostatically shield the charged motif, which increases structural stability.

    • Mona Baumgart
    • , Michael Röpke
    •  & Ville R. I. Kaila
  • Article
    | Open Access

    Realizing wearable sensors for blood pressure (BP) monitoring with clinically-acceptable performance remains a significant challenge. Here, the authors report a continuous noninvasive blood pressure measurement system featuring a volume control technique for small wearable sensors.

    • Jürgen Fortin
    • , Dorothea E. Rogge
    •  & Bernd Saugel
  • Article
    | Open Access

    In cells, DNA is arranged into topologically-constrained (supercoiled) structures, but how this supercoiling affects the detailed double-helical structure of DNA remains unclear. Here authors use atomic force microscopy and atomistic molecular dynamics simulations, to resolve structures of negatively-supercoiled DNA minicircles at base-pair resolution.

    • Alice L. B. Pyne
    • , Agnes Noy
    •  & Sarah A. Harris
  • Article
    | Open Access

    Structures of mu-opioid receptor (mOR) in complex with morphine derivatives have been determined; but the structural basis of mOR activation by fentanyl-like synthetic opioids remains unclear. Here, authors use state-of-the-art simulation techniques and discover a secondary binding mode which is only accessible when the conserved His297 adopts a neutral HID tautomer state.

    • Quynh N. Vo
    • , Paween Mahinthichaichan
    •  & Christopher R. Ellis
  • Article
    | Open Access

    Mapping free energy landscapes of complex multi-funneled metamorphic proteins and weakly-funneled intrinsically disordered proteins (IDPs) remains challenging. Here authors present a parallel-tempering method that takes advantage of accelerated water dynamics for efficient and accurate conformational sampling across a wide variety of proteins.

    • Rajeswari Appadurai
    • , Jayashree Nagesh
    •  & Anand Srivastava
  • Article
    | Open Access

    Recent advances in computational methods have enabled the predictive design of self-assembling protein nanomaterials with atomic-level accuracy. Here authors investigate the assembly of two computationally designed, 120-subunit icosahedral complexes and find that assembly of each material from its two constituent protein building blocks was highly cooperative.

    • Adam J. Wargacki
    • , Tobias P. Wörner
    •  & Neil P. King
  • Article
    | Open Access

    Archaerhodopsin-3 (AR3) mutants are commonly used in optogenetics for neuron silencing and membrane voltage sensing. High-resolution crystal structures show that desensitization of the AR3 photoreceptor occurs when internal hydrogen-bonded water networks are modified in response to changes in chromophore isomerization.

    • Juan F. Bada Juarez
    • , Peter J. Judge
    •  & Anthony Watts
  • Article
    | Open Access

    Balancing high resolution and broad genome coverage in single-cell Hi-C approaches remains challenging. Here, the authors describe a computational method for the reconstruction of a large 3D-ensemble of single-cell chromatin conformations from population Hi-C measurements and apply this model to study embryogenesis in Drosophila.

    • Qiu Sun
    • , Alan Perez-Rathke
    •  & Jie Liang
  • Article
    | Open Access

    Computational approaches to predict water’s role in host-ligand binding attract a great deal of attention. Here the authors use a metadynamics enhanced sampling method and machine learning to compute binding energies for host-guest systems from the SAMPL5 challenge and provide details of water structural changes.

    • Valerio Rizzi
    • , Luigi Bonati
    •  & Michele Parrinello
  • Article
    | Open Access

    Catch bonds are protein–ligand interactions that exhibit enhancement of bond lifetime when subject to tensile force, which is a desirable yet elusive attribute for man-made nanoparticle interfaces. Here, the authors provide a nanoparticle design that can form catch bonds with tunable force-enhanced lifetimes under thermal excitations.

    • Kerim C. Dansuk
    •  & Sinan Keten
  • Article
    | Open Access

    The authors present a method for calculating the accuracy of an NMR structure, where flexibility from backbone chemical shifts is compared to structural flexibility predicted using rigidity theory. The authors validate their method and use it to compare the accuracy of NMR and X-ray structures.

    • Nicholas J. Fowler
    • , Adnan Sljoka
    •  & Mike P. Williamson
  • Article
    | Open Access

    Cell proliferation is regulated by cell volume, but it is unclear how individual cancer cells coordinate to regulate cell volumes in 3D clusters. Here the authors propose a mechano-osmotic model to analyse the exchange of fluid and ions between connected cells and their environment in response to proliferation-induced solid stress.

    • Eoin McEvoy
    • , Yu Long Han
    •  & Vivek B. Shenoy
  • Article
    | Open Access

    Respiratory complex I plays a key role in energy metabolism. Cryo-EM structure of a mutant accessory subunit LYRM6 from the yeast Yarrowia lipolytica and molecular dynamics simulations reveal conformational changes at the interface between LYRM6 and subunit ND3, propagated further into the complex. These findings offer insight into the mechanism of proton pumping by respiratory complex I.

    • Etienne Galemou Yoga
    • , Kristian Parey
    •  & Heike Angerer
  • Article
    | Open Access

    The analysis of biomolecular frustration yielded insights into several aspects of protein behavior. Here the authors describe a framework to efficiently quantify and localize biomolecular frustration within proteins at atomic resolution, and observe that drug specificity is correlated with a minimally frustrated binding pocket leading to a funneled binding landscape.

    • Mingchen Chen
    • , Xun Chen
    •  & Peter G. Wolynes
  • Article
    | Open Access

    To overcome the limitation of FRET data being too sparse to cover all structural details, FRET experiments need to be carefully designed and complemented with simulations. Here the authors present a toolkit for automated design of FRET experiments, which determines how many and which FRET pairs should be used to maximize the accuracy, and for FRET-assisted structural modeling and refinement at the atomistic level.

    • Mykola Dimura
    • , Thomas-Otavio Peulen
    •  & Holger Gohlke
  • Article
    | Open Access

    In high fidelity DNA polymerases the exonuclease site is distal from the polymerization site and it is unknown how the primer strand travels between the two sites when mis-incorporated nucleotides must be removed. Here, the authors perform MD simulations and identify an optimal path for DNA primer strand translocation in the E. coli replicative DNA polymerase III and characterise the kinetics and dynamics of the Pol III pol-to-exo mode transition, which is validated with mutagenesis experiments.

    • Thomas Dodd
    • , Margherita Botto
    •  & Ivaylo Ivanov
  • Article
    | Open Access

    The protein translation machinery is the most expensive cellular subsystem in fast growing bacteria. Providing a detailed mechanistic model for this complex system, the authors show that the translation machinery components are expressed such that their combined cost to the cell is minimal.

    • Xiao-Pan Hu
    • , Hugo Dourado
    •  & Martin J. Lercher
  • Article
    | Open Access

    Living cells and tissues experience various complex modes of forces but how different force modes impact gene expression is elusive. Here authors apply forces via magnetic beads to integrins on a cell surface and observe force-mode dependent chromatin stretching and gene upregulation in cells and identify underlying mechanisms.

    • Fuxiang Wei
    • , Xiangyu Xu
    •  & Ning Wang
  • Article
    | Open Access

    There is a great interest in retrieving functional pathways from cryo-EM single-particle data. Here, the authors present an approach that combines cryo-EM with advanced data-analytical methods and molecular dynamics simulations to reveal the functional pathways traversed on experimentally derived energy landscapes using the ryanodine receptor type 1 as an example.

    • Ali Dashti
    • , Ghoncheh Mashayekhi
    •  & Abbas Ourmazd
  • Article
    | Open Access

    DNA glycosylases are lesion-specific enzymes that recognize specific nucleobase damages and catalyze their excision through cleavage of the glycosidic bond. Here, the authors present the crystal structures of human 8-oxoguanine (oxoG) DNA glycosylase bound to undamaged DNA and to DNA containing an intrahelical oxoG lesion and further analyse these structures with molecular dynamics simulations, which allows them to characterise the base-extrusion pathways.

    • Uddhav K. Shigdel
    • , Victor Ovchinnikov
    •  & Gregory L. Verdine
  • Article
    | Open Access

    The computational prediction of protein allostery can guide experimental studies of protein function and cellular activity. Here, the authors develop a network-based method to detect allosteric coupling within proteins solely based on their structures, and set up a webserver for allostery prediction.

    • Jian Wang
    • , Abha Jain
    •  & Nikolay V. Dokholyan
  • Article
    | Open Access

    The physical origins of man-made tissue morphologies with organ-like microscopic anatomy and functionality remain poorly understood. Here, authors propose a mechanistic theory of these structures, employing a 3D vertex model to reproduce the characteristic morphologies such as branched shapes.

    • Jan Rozman
    • , Matej Krajnc
    •  & Primož Ziherl
  • Article
    | Open Access

    Microtubules are dynamic tubulin polymers which elongate by addition of bent guanosine triphosphate tubulin to the tips of curving protofilaments. Here authors use Brownian dynamics modeling and electron cryotomography to show that the lateral activation energy barrier in tubulin-tubulin interactions is a key parameter for this process, controlling the development of high pulling forces.

    • Nikita B. Gudimchuk
    • , Evgeni V. Ulyanov
    •  & J. Richard McIntosh
  • Article
    | Open Access

    Zika xrRNAs survive in host cells because they can be unwound and copied by replicases, but resist degradation by exonucleases. Here authors use atomistic models and simulations and uncover that pulling into a pore the xrRNA $${3}^{\prime}$$ 3 end, as done by replicases, causes progressive unfolding; pulling the $${5}^{\prime}$$ 5 end, as done by exonucleases, triggers molecular tightening.

    • Antonio Suma
    • , Lucia Coronel
    •  & Cristian Micheletti
  • Article
    | Open Access

    Computer-aided design of protein-ligand binding is important for the development of novel drugs. Here authors present an approach to use the recently re-parametrized coarse-grained Martini model to perform unbiased millisecond sampling of protein-ligand binding interactions of small drug-like molecules.

    • Paulo C. T. Souza
    • , Sebastian Thallmair
    •  & Siewert J. Marrink
  • Article
    | Open Access

    Explicit molecular modelling of biological membrane systems is computationally expensive due to the large number of solvent particles and slow membrane kinetics. Here authors present a framework for integrating coarse-grained membrane models with continuum-based hydrodynamics which facilitates efficient simulation of large biomembrane systems.

    • Mohsen Sadeghi
    •  & Frank Noé
  • Article
    | Open Access

    Computer simulations of large-scale changes in membrane shape are challenging since they occur across a wide range of spatiotemporal scales. Here, authors present a multiscale algorithm that backmaps a continuum membrane model represented as a dynamically triangulated surface to its corresponding molecular model based on the coarse-grained Martini force field.

    • Weria Pezeshkian
    • , Melanie König
    •  & Siewert J. Marrink