Computational biophysics articles within Nature Communications

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  • Article
    | Open Access

    Many viral proteins are thought to be unlikely candidates for drug discovery as they lack obvious drug binding sites. Here, the authors use computational approaches followed by experimental validation to identify a cryptic pocket within the Ebola virus protein VP35.

    • Matthew A. Cruz
    • , Thomas E. Frederick
    •  & Gregory R. Bowman

  • Article
    | Open Access

    RNA molecules exhibit conformational fluctuations between ground states and excited states. Here the authors designed and verified small hairpin RNAs with predefined secondary structure reshufflings. In light of Van’t Hoff analysis and accelerated molecular dynamics simulation, a mechanism of multistep sequential transition has been revealed.

    • Ge Han
    •  & Yi Xue

  • Article
    | Open Access

    RNA folding free energy nearest neighbor parameters were determined for sequences with the nucleotide m6A. The RNAstructure software package can accommodate modified nucleotides, enabling secondary structure prediction of sequences with m6A.

    • Elzbieta Kierzek
    • , Xiaoju Zhang
    •  & David H. Mathews

  • Article
    | Open Access

    Morphogen gradients encode positional information during development. Here the authors use theory and simulations to suggest a positional accuracy of single gradients that directly explains the observed precision of progenitor domain boundaries.

    • Roman Vetter
    •  & Dagmar Iber

  • Article
    | Open Access

    While artificial intelligence (AI) is quickly becoming ubiquitous, biology still suffers from the lack of interfaces connecting biological structures and modern AI methods. Here, the authors report PyUUL, a library to translate biological structures into 3D differentiable tensorial representations.

    • Gabriele Orlando
    • , Daniele Raimondi
    •  & Frederic Rousseau

  • Article
    | Open Access

    The molecular determinants of the residence time of a small molecule inhibitor at its target protein are not well understood. Here, Pantsar et al. show that the target protein’s conformational stability and solvent exposure are key factors governing the target residence time of kinase inhibitors.

    • Tatu Pantsar
    • , Philipp D. Kaiser
    •  & Stefan A. Laufer

  • Article
    | Open Access

    To facilitate the rational design of (nano)-materials and biomacromolecules by MD simulations, the authors present the polyply suite, featuring a graph matching algorithm and a random walk protocol for generating multi-scale polymeric topologies and initial coordinates.

    • Fabian Grünewald
    • , Riccardo Alessandri
    •  & Siewert J. Marrink

  • Article
    | Open Access

    The authors present a strategy to construct dynamic biomolecular landscapes. Here, they derive a quantitative description of the distribution timescales and amplitudes of reorientational motion of POPC membranes from the combination of NMR relaxation data and frame analysis of MD simulations.

    • Albert A. Smith
    • , Alexander Vogel
    •  & Daniel Huster

  • Article
    | Open Access

    Nonphotochemical quenching (NPQ) protects photosynthetic complexes from damage due to excess light. Here the authors explore different conformations of the plant CP29 light harvesting complex, showing how protein tuning of carotenoid excitation energies and carotenoid-chlorophyll interactions account for NPQ.

    • Edoardo Cignoni
    • , Margherita Lapillo
    •  & Benedetta Mennucci

  • Article
    | Open Access

    UvrD is a model helicase from the non-hexameric Superfamily 1. Here, the authors use optical tweezers to measure directly the stepwise translocation of UvrD along a DNA hairpin, and propose a mechanism in which UvrD moves one base pair at a time, but sequesters the nascent single strands, releasing them after a variable number of ATP hydrolysis cycles.

    • Sean P. Carney
    • , Wen Ma
    •  & Yann R. Chemla

  • Article
    | Open Access

    Here, the authors combine single-molecule atomic force spectroscopy measurements and molecular dynamics simulations to investigate the binding of spike proteins from four SARS-CoV-2 variants of concern (VoC) to the human ACE2 receptor. They observe an increase in the RBD-ACE2 complex stability for several of the VoCs and derive how the mutations affect the kinetic, thermodynamic and structural properties of complex formation.

    • Melanie Koehler
    • , Ankita Ray
    •  & David Alsteens

  • Article
    | Open Access

    Many organs and cells have complex tree-like morphologies, but how these patterns emerge during development from global guidance cues and local self-organization remains unclear. Here, the authors develop a theory for the influence of both factors and test it on neuronal branching data.

    • Mehmet Can Uçar
    • , Dmitrii Kamenev
    •  & Edouard Hannezo

  • Article
    | Open Access

    Nuclear bodies are membraneless condensates that may form via liquid-liquid phase separation; however, they defy theoretical predictions where the equilibrium state should consist of a single droplet. Here the authors use a diploid human genome model parameterized with Hi-C data to simulate nucleoli formation. Their model suggests the chromatin network allows for existence of multiple droplets.

    • Yifeng Qi
    •  & Bin Zhang

  • Article
    | Open Access

    Fusion of cellular membranes begins with the formation of a stalk. Here, the authors develop a computationally efficient method for coarse-grained simulations of stalk formation and apply this approach to comprehensively analyse how stalk formation is influenced by the membrane lipid composition.

    • Chetan S. Poojari
    • , Katharina C. Scherer
    •  & Jochen S. Hub

  • Article
    | Open Access

    Amphiphysin BAR proteins reshape membranes, but the dynamics of the process remained unexplored. Here, the authors show through experiment and modelling that reshaping depends on the initial template shape, occurs even at low initial curvature, and involves the coexistence of isotropic and nematic states.

    • Anabel-Lise Le Roux
    • , Caterina Tozzi
    •  & Pere Roca-Cusachs

  • Article
    | Open Access

    Lysine acetylation regulates the function of soluble proteins in vivo, yet it remains largely unexplored whether lysine acetylation regulates the function of membrane proteins. Here, the authors map lysine acetylation predominantly in membrane-interaction regions in peripheral membrane proteins and show with three candidate proteins how lysine acetylation is a regulator of membrane protein function.

    • Alan K. Okada
    • , Kazuki Teranishi
    •  & Ralf Langen

  • Article
    | Open Access

    Deep learning (DL) can be used to automatically extract complex features from dynamic systems. Here, the authors combine high-content imaging, DL and mechanistic models to extract and explain drug-induced morphological changes in the growth of the fungus responsible for Asian soybean rust.

    • Henry Cavanagh
    • , Andreas Mosbach
    •  & Robert G. Endres

  • Article
    | Open Access

    Mesenchymal stem cells adopt differentiation pathways based upon mechanical cues in their environment which change throughout development. Here the authors develop a material and culture system to modify and measure the degree to which cells retain cumulative effects of mechanosensing to explore how cells erase the memory of some cues while locking in memory of others.

    • Cheng Zhang
    • , Hongyuan Zhu
    •  & Min Lin

  • Article
    | Open Access

    Although much effort has been devoted to determine the 3D structure of chromatin, there is a need for new experimental and computational methods. Here the authors present GP-FBM to extract chromatin diffusion parameters with high precision and apply it to live-imaging of embryonic stem cells, revealing that the diffusive properties of mitotic and interphase chromatin do not differ significantly.

    • Guilherme M. Oliveira
    • , Attila Oravecz
    •  & Nacho Molina

  • 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

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