Molecular modelling articles within Nature Communications

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  • 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

    TMEM16 lipid scramblases transport lipids and also operate as ion channels with highly variable ion selectivities and various physiological functions. Using computational electrophysiology simulations, the authors identify the main ion-conductive state of TMEM16 lipid scramblases and find that lipid headgroups modulate ion permeability and regulate ion selectivity of TMEM16 proteolipidic pores.

    • Andrei Y. Kostritskii
    •  & Jan-Philipp Machtens

  • Article
    | Open Access

    As part of two-component systems, diguanylate cyclases (DGCs) are activated by phosphorylation. Structural and computational analyses of DgcR, a model DGC, reveal the phosphorylation-induced conformational changes and the activation mechanism likely shared by many DGCs with N-terminal coiled-coil linkers.

    • Raphael D. Teixeira
    • , Fabian Holzschuh
    •  & Tilman Schirmer

  • Article
    | Open Access

    The Hsp70/Hsp40 system plays an important role in maintaining cellular proteostasis but so far it is not well understood how Hsp70 proteins are recruited to specific Hsp40 co-chaperones. Here, the authors combine biochemical and biophysical approaches to characterise the oligomeric mammalian Hsp40 DnaJB8. They identify an intra-oligomer DnaJB8 interaction between the N-terminal J-Domain and the C-terminal domain that occludes the J-Domain surface that binds Hsp70 and propose a model for DnaJB8-Hsp70 recruitment.

    • Bryan D. Ryder
    • , Irina Matlahov
    •  & Lukasz A. Joachimiak

  • Article
    | Open Access

    The tumor suppressor p53 is a master regulator of cellular stress response pathways, including cell cycle arrest and apoptosis. Here, the authors identify molecular mechanisms of p53 binding to high- and low-affinity p53 response elements in the genome, linked to cell cycle arrest and pro-apoptotic genes, respectively.

    • Marina Farkas
    • , Hideharu Hashimoto
    •  & Steven B. McMahon

  • Article
    | Open Access

    Most approaches for modeling the membrane protein complexes are not capable of incorporating the topological information provided by the membrane. Here authors present an integrative computational protocol for the modeling of membrane-associated protein assemblies, specifically complexes consisting of a membrane-embedded protein and a soluble partner.

    • Jorge Roel-Touris
    • , Brian Jiménez-García
    •  & Alexandre M. J. J. Bonvin

  • Article
    | Open Access

    Cyclohexadienyl dehydratase (CDT) evolved from a cationic amino acid binding protein ancestor without enzymatic activity (AncCDT-1) via a series of intermediates. Here, the authors combine EPR, X-ray crystallography and MD simulations to study the structural dynamics of these evolutionary intermediates and observe that they predominantly populate catalytically unproductive conformations, while CDT exclusively samples catalytically relevant compact states, and which reveals how the conformational landscape changes along the evolutionary trajectory.

    • Joe A. Kaczmarski
    • , Mithun C. Mahawaththa
    •  & Colin J. Jackson

  • Article
    | Open Access

    So far only a few compounds have been reported as splicing modulators. Here, the authors combine high-throughput screening, chemical synthesis, NMR, X-ray crystallography with functional studies and develop phenothiazines as inhibitors for the U2AF Homology Motif (UHM) domains of proteins that regulate splicing and show that they inhibit early spliceosome assembly on pre-mRNA substrates in vitro.

    • Pravin Kumar Ankush Jagtap
    • , Tomáš Kubelka
    •  & Michael Sattler

  • Article
    | Open Access

    As protein synthesis takes place, newly synthesized polypeptide chain passes through the ribosomal exit tunnel, which can accommodate up to 70 residues in the case of a helical peptide. Here the authors show that oxidation of cysteine residues in the nascent chain can occur within the ribosome exit tunnel, where sufficient space exists for the formation of disulfide bonds.

    • Linda Schulte
    • , Jiafei Mao
    •  & Harald Schwalbe

  • 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

    Transcriptional biosensors represent powerful tools for the screening of vast strain libraries, but the broad ligand specificity of some transcriptional regulators (TRs) can prohibit such applications. Here authors present the engineering of a LysG-based biosensor with a focused ligand specificity to isolate L-histidine-producing strains.

    • Dennis Della Corte
    • , Hugo L. van Beek
    •  & Jan Marienhagen

  • Article
    | Open Access

    The local lipid environment is known to affect the structure, stability and intercellular channel activity of gap junctions, however, the molecular basis for these effects remains unknown. Here authors report the CryoEM structure of Cx46/50 lipid-embedded channels, by which they reveal a lipid-induced stabilization to the channel.

    • Jonathan A. Flores
    • , Bassam G. Haddad
    •  & Steve L. Reichow

  • Article
    | Open Access

    An increasing number of amyloid structures are determined. Here, the authors present the structure-based amyloid core sequence prediction method Cordax that is based on machine learning and allows the detection of aggregation-prone regions with higher solubility, disorder and surface exposure, and furthermore predicts the structural topology, orientation and overall architecture of the resulting putative fibril core.

    • Nikolaos Louros
    • , Gabriele Orlando
    •  & Joost Schymkowitz

  • Article
    | Open Access

    Formaldehyde (FA) is a popular cross-linking reagent, but applying it for cross-linking mass spectrometry (XLMS) has been largely unsuccessful. Here, the authors show that cross-links in structured proteins are the product of two FA molecules and identify hundreds of FA cross-links by XLMS in vitro and in situ.

    • Tamar Tayri-Wilk
    • , Moriya Slavin
    •  & Nir Kalisman

  • 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

    The serotonin transporter (SERT) terminates serotonin signaling and its activity is modulated by antidepressants. Here authors reveal the mechanistic details underlying the coupling between the two binding sites in SERT and a high-affinity ligand for the allosteric site.

    • Per Plenge
    • , Ara M. Abramyan
    •  & Claus J. Loland

  • Article
    | Open Access

    The chaperone Hsp90 uses the free energy from ATP hydrolysis to control the folding of client proteins in eukaryotic cells. Here the authors provide mechanistic insights into how its catalytic activity is coupled to conformational changes by combining large-scale molecular simulations with NMR, FRET and SAXS experiments.

    • Sophie L. Mader
    • , Abraham Lopez
    •  & Ville R. I. Kaila

  • Article
    | Open Access

    Major Histocompatibility Complex (MHC) class I molecules present tightly binding peptides on the cell surface for recognition by cytotoxic T cells. Here, the authors present the crystal structures of a disulfide-stabilized human MHC class I molecule in the peptide-free state and bound with dipeptides, and find that peptide binding is accompanied by concerted conformational switches of the amino acid side chains in the binding pockets.

    • Raghavendra Anjanappa
    • , Maria Garcia-Alai
    •  & Rob Meijers

  • Article
    | Open Access

    RNA polymerase I (Pol I) catalyses the transcription of ribosomal RNA precursors, and its transcription initiation mechanism differs from that of Pol II and Pol III. Here the authors present the cryo-EM structure of a trapped early intermediate stage of promoter-recruited Pol I, which reveals the interactions of the basal rDNA transcription machinery with the native promoter, and discuss the mechanistic implications.

    • Michael Pilsl
    •  & Christoph Engel

  • Article
    | Open Access

    The Staufen proteins recognize secondary structures in 3’-untranslated regions in mRNA transcripts and induce degradation of these mRNAs with the help of the RNA helicase UPF1. Here the authors report that the nonsense-mediated mRNA decay factor UPF2 mediates the interaction between Stau1 and UPF1 in Staufen-mediated mRNA decay.

    • Manjeera Gowravaram
    • , Juliane Schwarz
    •  & Sutapa Chakrabarti

  • 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 fraction of protein-protein interactions (PPIs) that can be disrupted without fitness effect is unknown. Here, the authors model how disease-causing mutations and common mutations carried by healthy people perturb the interactome, and estimate that <20% of human PPIs are completely dispensable.

    • Mohamed Ghadie
    •  & Yu Xia

  • Article
    | Open Access

    Ric8A regulates G protein α-subunits (Gα) by acting as a guanine nucleotide exchange factor (GEF) and a Gα chaperone. Here, the authors solve the crystal structures of free and Gα fragment bound Ric8A, and provide insights into the structural basis for Ric8A’s GEF and chaperone functions.

    • Dhiraj Srivastava
    • , Lokesh Gakhar
    •  & Nikolai O. Artemyev

  • Article
    | Open Access

    Lamin A is critical for nuclear architecture but its structure and assembly are not fully understood. Here, the authors use quantitative cross-linking mass spectrometry to map intra- and intermolecular interactions within lamin homomers, providing insights into the molecular basis for lamin’s mechanical properties.

    • Alex A. Makarov
    • , Juan Zou
    •  & Eric C. Schirmer

  • Article
    | Open Access

    Enzyme substrates and products often diffuse too rapidly to assess the catalytic implications of these movements. Here, the authors characterise the structural basis of product and substrate diffusion for an exo-hydrolase and discover a substrate-product assisted processive catalytic mechanism.

    • Victor A. Streltsov
    • , Sukanya Luang
    •  & Maria Hrmova

  • Article
    | Open Access

    Ubiquitination of histone H2A can occur on distinct lysine residues, but how each site is recognised by the specific E3 ligase remains poorly understood. Here the authors demonstrate that the E3 ligase RNF168 binds the acidic patch on the nucleosome surface, directing the E2 to the target lysine K13/K15.

    • Velten Horn
    • , Michael Uckelmann
    •  & Hugo van Ingen

  • Article
    | Open Access

    The Ups/PRELI family mediates intramitochondrial lipid distribution and synthesis by shuttling phospholipids between both mitochondrial membranes. Here the authors combine X-ray crystallography, MD simulations and yeast genetic screens and identify residues that are important for Ups/PRELI lipid specificity and reveal a dual lipid recognition mechanism in Ups/PRELI family members.

    • Xeni Miliara
    • , Takashi Tatsuta
    •  & Thomas Langer

  • Article
    | Open Access

    Protein structure determination in complex biological samples is still challenging. Here, the authors develop a computational modeling-guided cross-linking mass spectrometry method, obtaining a high-resolution model of a 1.8 MDa protein assembly from cross-links detected in a mixture of human plasma and bacteria.

    • Simon Hauri
    • , Hamed Khakzad
    •  & Lars Malmström

  • Article
    | Open Access

    The activity of several protein kinases is increased upon cellular production of reactive oxygen species, which can cause cysteine oxidation. Here the authors show that sulfenylation of specific cysteine residues within Src induce local structural changes that directly impact its activation.

    • David E. Heppner
    • , Christopher M. Dustin
    •  & Albert van der Vliet

  • Article
    | Open Access

    The bacterial diterpene synthase CotB2 catalyses the cyclisation of geranylgeranyl diphosphate to cyclooctat-9-en7-ol. Here the authors present various CotB2 structures including a trapped abrupt reaction product that were used for molecular dynamic simulations and allowed them to model all intermediates along the reaction cascade.

    • Ronja Driller
    • , Sophie Janke
    •  & Bernhard Loll

  • Article
    | Open Access

    Single-particle cryo-EM is a powerful method for macromolecular structure determination. Here the authors demonstrate that Ewald sphere curvature correction, sub-Angstrom pixilation and per-particle CTF refinement can improve map quality and resolution and present the 1.86 Å cryo-EM structure of an adeno-associated virus serotype 2 variant.

    • Yong Zi Tan
    • , Sriram Aiyer
    •  & Dmitry Lyumkis

  • Article
    | Open Access

    Some TMEM16 family members are Ca2+-dependent phospholipid scramblases, which also mediate non-selective ion transport; however, the mechanism how lipids permeate through the TMEM16 remains poorly understood. Here, the authors combine biochemical assays and simulations to identify the key steps regulating lipid movement through the membrane-exposed groove.

    • Byoung-Cheol Lee
    • , George Khelashvili
    •  & Alessio Accardi

  • Article
    | Open Access

    Computationally designed enzymes often show lower activity or stability than their natural counterparts. Here, the authors present an evolution-inspired method for automated enzyme design, creating stable enzymes with accurate active site architectures and wild-type-like activities.

    • Gideon Lapidoth
    • , Olga Khersonsky
    •  & Sarel J. Fleishman

  • Article
    | Open Access

    The liver-specific microRNA-122 is an essential proviral host factor of Hepatitis C virus replication. Here the authors show that microRNA-122 functions as an RNA chaperone that guides the formation of a functional internal ribosome entry site by preventing energetically more favorable secondary structures within the HCV RNA genome.

    • Philipp Schult
    • , Hanna Roth
    •  & Volker Lohmann

  • Article
    | Open Access

    Acid-sensing ion channels (ASICs) sense changes in extracellular acidity with Ca2+ as an allosteric modulator and channel blocker. Here authors use electrophysiology and molecular dynamics simulation to identify the residue in ASIC3 which modulates proton sensitivity and contributes to the Ca2+ block.

    • Zhicheng Zuo
    • , Rachel N. Smith
    •  & Eric B. Gonzales

  • Article
    | Open Access

    Spinal muscular atrophy (SMA) is an autosomal recessive disorder with no present cure. Here the authors perform an in vitro screening leading to the identification of a small molecule that alters the conformational dynamics of the TSL2 RNA structure and acts as a modulator of SMN exon 7 splicing.

    • Amparo Garcia-Lopez
    • , Francesca Tessaro
    •  & Leonardo Scapozza

  • Article
    | Open Access

    The aggregation prone D76N beta-2 microglobulin mutant causes systemic amyloidosis. Here the authors combine crystallography, solid-state NMR, and computational studies and show that the D76N mutation increases protein dynamics and destabilizes the outer strands, which leads to an exposure of amyloidogenic parts explaining its aggregation propensity.

    • Tanguy Le Marchand
    • , Matteo de Rosa
    •  & Stefano Ricagno

  • Article
    | Open Access

    Extracting kinetic models from high-throughput molecular dynamics (MD) simulations is laborious and prone to human error. Here the authors introduce a deep learning framework that automates construction of Markov state models from MD simulation data.

    • Andreas Mardt
    • , Luca Pasquali
    •  & Frank Noé

  • Article
    | Open Access

    Ligand-induced biased signaling is thought to result in part from ligand-specific receptor conformations that cause the engagement of distinct effectors. Here the authors trace and evaluate the impact of mutations of the β2–adrenergic receptor on multiple signaling outputs to provide structural-level insight into the determinants of GPCR functional selectivity.

    • Anne-Marie Schönegge
    • , Jonathan Gallion
    •  & Michel Bouvier

  • 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

    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

    N-methyl D-aspartate receptor (NMDAR) activity is modulated by Src tyrosine kinase via the mitochondrial protein NADH dehydrogenase subunit 2 (ND2). Here the authors show that ND2 interacts with the transmembrane region of NMDAR GluN1 subunit, a process that is crucial for Src regulation of NMDAR activity.

    • David P. Scanlon
    • , Alaji Bah
    •  & Michael W. Salter

  • Article
    | Open Access

    The three-dimensional architecture of genome-reduced bacteria is poorly understood. Here the authors combine Hi-C with super-resolution microscopy inMycoplasma pneumoniaeand provide evidence of how supercoiling and local organization influences gene regulation.

    • Marie Trussart
    • , Eva Yus
    •  & Luís Serrano

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