Computational biophysics articles within Nature Communications

Featured

• Article
  21 June 2023 | Open Access

  How soluble misfolded proteins bypass chaperones at the molecular level

  How soluble misfolded proteins can bypass chaperones is unknown. Utilizing a meta-analysis, multi-scale modelling, and new experimental data it is found that this phenomena is common and arises from misfolded states that are native-like and long-lived due to protein self-entanglements.

  • Ritaban Halder
  • , Daniel A. Nissley
  •  & Edward P. O’Brien

• Article
  19 June 2023 | Open Access

  Structure and dynamics of an archetypal DNA nanoarchitecture revealed via cryo-EM and molecular dynamics simulations

  DNA can be folded into rationally designed, unique, and functional materials. Here the authors analyse an archetypal DNA nanoarchitecture with single particle cryo-electron microscopy and molecular dynamics simulations.

  • Katya Ahmad
  • , Abid Javed
  •  & Stefan Howorka

• Article
  09 June 2023 | Open Access

  Substrate binding-induced conformational transitions in the omega-3 fatty acid transporter MFSD2A

  Molecular mechanisms of MFSD2A-mediated lysolipid transport into the brain has been elusive. Here, using molecular dynamics, the authors uncover how initial stages of transport cycle are enabled by substrate-induced conformational changes in MFSD2A.

  • Shana Bergman
  • , Rosemary J. Cater
  •  & George Khelashvili

• Article
  09 June 2023 | Open Access

  Inflationary theory of branching morphogenesis in the mouse salivary gland

  The authors show that the ramified ductal network of the mouse salivary gland develops from a set of simple probabilistic rules, where ductal elongation and branching are driven by the persistent expansion of the surrounding tissue.

  • Ignacio Bordeu
  • , Lemonia Chatzeli
  •  & Benjamin D. Simons

• Article
  22 May 2023 | Open Access

  Chemo-mechanical diffusion waves explain collective dynamics of immune cell podosomes

  Dendritic cells can utilize the dynamics of podosomes to probe their microenvironment. Here, the authors propose a chemo-mechanical model for the height oscillations of individual podosomes and the collective wave dynamics in a podosome cluster.

  • Ze Gong
  • , Koen van den Dries
  •  & Vivek B. Shenoy

• Article
  17 May 2023 | Open Access

  Structural basis of epitope selectivity and potent protection from malaria by PfCSP antibody L9

  The cryo-EM structure of the highly potent malaria antibody L9 reveals a key role of light-chain derived homotypic interactions in antigen binding and parasite inhibition, enabling antibody engineering and next-generation malaria vaccine design.

  • Gregory M. Martin
  • , Monica L. Fernández-Quintero
  •  & Andrew B. Ward

• Article
  13 May 2023 | Open Access

  Dynamic conformational switching underlies TFIIH function in transcription and DNA repair and impacts genetic diseases

  The study unveils the structure, dynamics and regulatory mechanisms of the TFIIH protein assembly underpinning its divergent functions in gene expression and genome maintenance. Models link positions of TFIIH mutations to genetic disease phenotypes.

  • Jina Yu
  • , Chunli Yan
  •  & Ivaylo Ivanov

• Article
  05 May 2023 | Open Access

  Molecular determinants of inhibition of UCP1-mediated respiratory uncoupling

  Combining molecular dynamic simulations with in vivo functional assays, Gagelin et al. identified unique molecular features of the mitochondrial carrier uncoupling protein 1 that are crucial to its inhibition by nucleotides

  • Antoine Gagelin
  • , Corentin Largeau
  •  & Bruno Miroux

• Article
  27 April 2023 | Open Access

  Automated design of protein-binding riboswitches for sensing human biomarkers in a cell-free expression system

  Cell-free genetically encoded biosensors have been developed to detect small molecules and nucleic acids, but they have yet to be reliably engineered to detect proteins. Here the authors develop an automated platform to convert protein-binding RNA aptamers into riboswitch sensors that operate within low-cost cell-free assays.

  • Grace E. Vezeau
  • , Lipika R. Gadila
  •  & Howard M. Salis

• Article
  22 April 2023 | Open Access

  Computational design and molecular dynamics simulations suggest the mode of substrate binding in ceramide synthases

  Membrane proteins are involved in many critical cellular pathways. Here, authors use a combination of structural predictions, an algorithm for stabilizing membrane proteins, and molecular dynamics to reveal a putative mechanism for the action of ceramide synthases.

  • Iris D. Zelnik
  • , Beatriz Mestre
  •  & Anthony H. Futerman

• Article
  19 April 2023 | Open Access

  Latent generative landscapes as maps of functional diversity in protein sequence space

  In this work, the authors study protein families’ VAE latent manifolds and coevolutionary Hamiltonians. These Latent Generative Landscapes predict phylogenetic groupings, fitness & functional properties for several systems with clear protein engineering/design potential.

  • Cheyenne Ziegler
  • , Jonathan Martin
  •  & Faruck Morcos

• Article
  19 April 2023 | Open Access

  Turning up the heat mimics allosteric signaling in imidazole-glycerol phosphate synthase

  Using a combination of MD simulations and NMR, the authors investigate how temperature affects allostery in imidazole glycerol phosphate synthase (IGPS), revealing that increase of temperature triggers local amino acid dynamics and providing insights into mechanism of allosteric regulation.

  • Federica Maschietto
  • , Uriel N. Morzan
  •  & Victor S. Batista

• Article
  17 April 2023 | Open Access

  Central cavity dehydration as a gating mechanism of potassium channels

  The hydrophobic gating is believed to function in various ion channels. Here, the authors use MD simulations to assess how dewetting of the channel pore modulates the function and conformational transition of the potassium channels.

  • Ruo-Xu Gu
  •  & Bert L. de Groot

• Article
  12 April 2023 | Open Access

  Collagen breaks at weak sacrificial bonds taming its mechanoradicals

  Collagen is an important structural protein in connective tissue, but the effect of location and type of micro-ruptures in the structure on the overall tissue is not well understood. Here, the authors use scale-bridging simulations to determine the breakage points in collagen, and how the failure mode helps to prevent material ageing

  • Benedikt Rennekamp
  • , Christoph Karfusehr
  •  & Frauke Gräter

• Article
  10 April 2023 | Open Access

  Performance efficient macromolecular mechanics via sub-nanometer shape based coarse graining

  Here the authors report SBCG2 an update to the neural network based, Shape-Based Coarse Graining (SBCG) approach for creating coarse grained molecular topologies with atomistic detail. They show how SBCG2 can reduce the computational costs of simulating very large assemblies like the HIV-1 capsid allowing simulation on commodity hardware.

  • Alexander J. Bryer
  • , Juan S. Rey
  •  & Juan R. Perilla

• Article
  03 April 2023 | Open Access

  Structure and mechanism of oxalate transporter OxlT in an oxalate-degrading bacterium in the gut microbiota

  In our gut, oxalate-degrading bacteria absorb oxalate, a causative substance for kidney stone formation, and reduce our health risk. In this work, the authors report the structure of the oxalate transporter responsible for this process and how the protein works.

  • Titouan Jaunet-Lahary
  • , Tatsuro Shimamura
  •  & Atsuko Yamashita

• Article
  23 March 2023 | Open Access

  A myoelectric digital twin for fast and realistic modelling in deep learning

  Muscle electrophysiology is a promising tool for human-machine approaches in medicine and beyond clinical applications. The authors propose here a model simulating electric signals produced during human movements and apply this data for training of deep learning algorithms.

  • Kostiantyn Maksymenko
  • , Alexander Kenneth Clarke
  •  & Dario Farina

• Article
  10 March 2023 | Open Access

  Intermediate-state-trapped mutants pinpoint G protein-coupled receptor conformational allostery

  Understanding of GPCR activation is limited as the structural information fails to present the full spectrum of energy landscape. Here, authors establish a series of conformation-biased mutants that represent five conformational states lying along adenosine A_2A receptor (A_2AR) activation.

  • Xudong Wang
  • , Chris Neale
  •  & Libin Ye

• Article
  01 March 2023 | Open Access

  Predicting locations of cryptic pockets from single protein structures using the PocketMiner graph neural network

  Cryptic pockets enable targeting of proteins currently considered undruggable because they lack pockets in their ground state structures. Here, the authors develop a graph neural network that accurately predicts cryptic pockets in static structures by training using molecular simulation data alone.

  • Artur Meller
  • , Michael Ward
  •  & Gregory R. Bowman

• Article
  01 March 2023 | Open Access

  A maximum-entropy model to predict 3D structural ensembles of chromatin from pairwise distances with applications to interphase chromosomes and structural variants

  Here the authors develop a computational method based on the maximum entropy principle to construct the structural ensemble of genomes using imaging data. The work reveals three-way contacts between loci and extensive conformational heterogeneity.

  • Guang Shi
  •  & D. Thirumalai

• Article
  01 March 2023 | Open Access

  Structural details of a Class B GPCR-arrestin complex revealed by genetically encoded crosslinkers in living cells

  The conformation of GPCR-arrestin complexes at the cell membrane, despite available structures, remains uncertain. This work reveals structure and dynamics of the PTH1R-arrestin2 complex, including flexible regions, in live cells.

  • Yasmin Aydin
  • , Thore Böttke
  •  & Irene Coin

• Article
  27 February 2023 | Open Access

  Noncanonical electromechanical coupling paths in cardiac hERG potassium channel

  Potassium channels allow vital organ such as brain, heart, and muscles to function. Here, authors reveal the existence of a noncanonical kinematic chain of residues involving the S4/S1 and S1/S5 subunit interfaces that controls the gating of the hERG cardiac channel.

  • Carlos A. Z. Bassetto Jr
  • , Flavio Costa
  •  & Alberto Giacomello

• Article
  16 February 2023 | Open Access

  Network of hotspot interactions cluster tau amyloid folds

  The authors developed a computational approach to probe the stability of amyloid fibrils and discover networks of hotspot interactions. Understanding the mechanisms of amyloid folding will help identify novel methods to treat protein (mis)folding diseases.

  • Vishruth Mullapudi
  • , Jaime Vaquer-Alicea
  •  & Lukasz A. Joachimiak

• Article
  11 February 2023 | Open Access

  Histone variant H2A.Z modulates nucleosome dynamics to promote DNA accessibility

  Here the authors show that H2A.Z histone variant incorporation reduces the nucleosomal barrier for transcription. Furthermore their simulations reveal that H2A.Z facilitates spontaneous DNA unwrapping from the histone octamer and enhances nucleosome gaping.

  • Shuxiang Li
  • , Tiejun Wei
  •  & Anna R. Panchenko

• Article
  11 February 2023 | Open Access

  Direct generation of protein conformational ensembles via machine learning

  Computational methods to study protein structural dynamics are a powerful tool in life sciences but are computationally expensive. Here, the authors show that machine learning can be used to efficiently generate protein conformational ensembles and test their method on intrinsically disordered peptides.

  • Giacomo Janson
  • , Gilberto Valdes-Garcia
  •  & Michael Feig

• Article
  04 February 2023 | Open Access

  Different pathways for engulfment and endocytosis of liquid droplets by nanovesicles

  In this work, the authors investigate on how condensate droplets, arising from liquid-liquid phase separation, can be engulfed by nanovesicles via distinct pathways, leading to different vesicle-droplet morphologies. Two key parameters are the stress asymmetry of the vesicle membrane and the line tension of the contact line between vesicle and droplet.

  • Rikhia Ghosh
  • , Vahid Satarifard
  •  & Reinhard Lipowsky

• Article
  27 January 2023 | Open Access

  Directing Min protein patterns with advective bulk flow

  Meindlhumer et al. report a combined theoretical/experimental study of how the propagation direction of Min protein patterns can be altered by a bulk flow of solution.

  • Sabrina Meindlhumer
  • , Fridtjof Brauns
  •  & Erwin Frey

• Article
  19 January 2023 | Open Access

  Interphase chromosomes of the Aedes aegypti mosquito are liquid crystalline and can sense mechanical cues

  Within the nucleus, the genome of eukaryotes folds into partially organized three-dimensional structures specific to each organism. Here the authors perform physical simulations to study the genome architecture of Aedes aegypti, which reveal an ensemble of 3D chromosomal structures that are folded over and partially condensed, resembling liquid crystalline properties.

  • Vinícius G. Contessoto
  • , Olga Dudchenko
  •  & Michele Di Pierro

• Article
  09 January 2023 | Open Access

  Thermodynamic architecture and conformational plasticity of GPCRs

  GPCRs are integral membrane proteins that serve as attractive drug targets. Here, authors delineate the conformational landscapes of 45 GPCRs using a statistical model, highlighting their malleable native ensembles and providing functional insights.

  • Sathvik Anantakrishnan
  •  & Athi N. Naganathan

• Article
  24 December 2022 | Open Access

  Force-tuned avidity of spike variant-ACE2 interactions viewed on the single-molecule level

  Combining high-speed AFM, single molecule recognition force spectroscopy, and molecular dynamics simulations Zhu, Canena, Sikora et al. characterize the interaction dynamics of the trimeric spike protein of SARS-CoV-2 wt, and delta and omicron variants with its entry receptor ACE2. While delta variant increases avidity by multivalent binding to ACE2, omicron variant shows an extended binding lifetime.

  • Rong Zhu
  • , Daniel Canena
  •  & Peter Hinterdorfer

• Article
  21 December 2022 | Open Access

  Protein complex prediction using Rosetta, AlphaFold, and mass spectrometry covalent labeling

  Covalent labeling (CL) from mass spectrometry experiments provides structural information of higher-order protein structure. Here, the authors develop an algorithm which integrates experimental CL data to predict protein complexes in the Rosetta molecular modeling suite using AlphaFold models.

  • Zachary C. Drake
  • , Justin T. Seffernick
  •  & Steffen Lindert

• Article
  13 December 2022 | Open Access

  Condensates formed by prion-like low-complexity domains have small-world network structures and interfaces defined by expanded conformations

  The authors provide a physical description for condensates as complex fluids defined by small-world network structures for their interiors, and of interfaces featuring a preference of locally and globally expanded conformations.

  • Mina Farag
  • , Samuel R. Cohen
  •  & Rohit V. Pappu

• Article
  09 December 2022 | Open Access

  Visualizing the transiently populated closed-state of human HSP90 ATP binding domain

  To refold client proteins, HSP90 chaperone undergoes large structural rearrangements. Here the authors use NMR and molecular simulation and reveal structure and dynamics of a key functionally relevant metastable state of human HSP90α N-terminal domain.

  • Faustine Henot
  • , Elisa Rioual
  •  & Jerome Boisbouvier

• Article
  09 December 2022 | Open Access

  Interpretable and tractable models of transcriptional noise for the rational design of single-molecule quantification experiments

  Here the authors explore the distributional differences expected from distinct biophysical models of transcription and show how measurements from single-cell genomics experiments can shed light on the underlying biological processes.

  • Gennady Gorin
  • , John J. Vastola
  •  & Lior Pachter

• Article
  05 December 2022 | Open Access

  Planar aggregation of the influenza viral fusion peptide alters membrane structure and hydration, promoting poration

  Target membrane poration is a longstanding enigma in virology. Here, authors show that fusion peptides of the influenza virus’ spike protein aggregate, rotate, and tilt in membranes, facilitating peptide-induced poration during viral fusion.

  • Amy Rice
  • , Sourav Haldar
  •  & Joshua Zimmerberg

• Article
  19 November 2022 | Open Access

  Feedback between mechanosensitive signaling and active forces governs endothelial junction integrity

  Gap formation in the vasculature underpins immune and tumour cell infiltration. Here the authors propose a chemo-mechanical model to analyse how feedback between mechanosensitive signalling, active cellular forces and adhesion governs the breakdown, recovery, and integrity of endothelial junctions.

  • Eoin McEvoy
  • , Tal Sneh
  •  & Vivek B. Shenoy

• Article
  19 November 2022 | Open Access

  Deep learning to decompose macromolecules into independent Markovian domains

  Modeling the dynamics of large proteins reveals a fundamental scaling problem. Here, the authors tackle this challenge by decomposing a large system into smaller independent subsystems, simultaneously modeling each subsystem’s kinetics and ensuring their mutual independence.

  • Andreas Mardt
  • , Tim Hempel
  •  & Frank Noé

• Article
  12 November 2022 | Open Access

  Lipid-mediated prestin organization in outer hair cell membranes and its implications in sound amplification

  Prestin, a motor protein, plays a major role in sound amplification. Using molecular dynamics simulations, the authors show that prestin causes membrane deformation patterns thereby achieving a particular lipid-mediated alignment in the membrane.

  • Sepehr Dehghani-Ghahnaviyeh
  • , Zhiyu Zhao
  •  & Emad Tajkhorshid

• Article
  11 November 2022 | Open Access

  Protein control of photochemistry and transient intermediates in phytochromes

  Phytochromes are photoreceptors responsible for sensing light in plants, fungi and bacteria. Here the authors use computational simulations to reveal the molecular mechanism of photoactivation and characterize the involved reaction intermediates.

  • Giacomo Salvadori
  • , Veronica Macaluso
  •  & Benedetta Mennucci

• Article
  09 November 2022 | Open Access

  An allosteric modulator activates BK channels by perturbing coupling between Ca²⁺ binding and pore opening

  Ca²⁺ activated BK channels are important for neural and muscle function. Here authors use a compound, BC5, to show that the interface between the cytosolic and voltage sensing domains is a major allosteric pathway for Ca²⁺ binding to open the channel.

  • Guohui Zhang
  • , Xianjin Xu
  •  & Jianmin Cui

• Article
  07 November 2022 | Open Access

  Robust replication initiation from coupled homeostatic mechanisms

  Homeostasis of DNA density is a hallmark of living cells. The authors show via mathematical modelling how two cycles, a titration-based concentration cycle and a nucleotide activation cycle, together drive replication in E. coli at all growth rates.

  • Mareike Berger
  •  & Pieter Rein ten Wolde

• Article
  27 October 2022 | Open Access

  Small molecules targeting the disordered transactivation domain of the androgen receptor induce the formation of collapsed helical states

  In this work the authors report atomically detailed computer simulations revealing the binding mechanisms of small molecule drugs to an intrinsically disordered region of the androgen receptor, a castration-resistant prostate cancer drug target.

  • Jiaqi Zhu
  • , Xavier Salvatella
  •  & Paul Robustelli

• Article
  20 October 2022 | Open Access

  Atomic resolution protein allostery from the multi-state structure of a PDZ domain

  In this manuscript the authors report accurate multi-state protein structures of the PDZ domain using biological NMR. By looking into protein structural states, the authors report an allosteric pathway at atomic resolution that validates previously reported low resolution findings and uncovered a structural hallmark of the allosteric ligand binding to the PDZ domain.

  • Dzmitry Ashkinadze
  • , Harindranath Kadavath
  •  & Roland Riek

• Article
  06 October 2022 | Open Access

  Predicting the structural basis of targeted protein degradation by integrating molecular dynamics simulations with structural mass spectrometry

  The formation of ternary degrader-protein complexes is a key step in the targeted degradation of proteins of interest. Here, the authors explore the structure and dynamics of such complexes applying high-performance computer simulations augmented with experimental data.

  • Tom Dixon
  • , Derek MacPherson
  •  & Jesus A. Izaguirre

• Article
  29 September 2022 | Open Access

  Protein structural transitions critically transform the network connectivity and viscoelasticity of RNA-binding protein condensates but RNA can prevent it

  In this work the authors propose a multiscale computational approach, integrating atomistic and coarse-grained models simulations, to study the thermodynamic and kinetic factors playing a major role in the liquid-to-solid transition of biomolecular condensates. It is revealed how the gradual accumulation of inter-protein β-sheets increases the viscosity of functional liquid-like condensates, transforming them into gel-like pathological aggregates, and it is also shown how high concentrations of RNA can decelerate such transition.

  • Andres R. Tejedor
  • , Ignacio Sanchez-Burgos
  •  & Jorge R. Espinosa

• Article
  26 September 2022 | Open Access

  Predictive model for cytoneme guidance in Hedgehog signaling based on Ihog- Glypicans interaction

  Cytonemes are specialized filopodia-like structures known to be involved in signal transduction. Here they propose a new predictive model for cytoneme guidance in Hedgehog signaling, which is based on Ihog, Dally, and Dlp protein levels.

  • Adrián Aguirre-Tamaral
  • , Manuel Cambón
  •  & Isabel Guerrero

• Article
  02 September 2022 | Open Access

  Proton-driven alternating access in a spinster lipid transporter

  The Spns lipid transporters use ion gradients to drive substrate transport, including bioactive sphingolipids. Here, Dastvan et al. investigated how binding of protons powers the conformational changes that enable broad transport by a bacterial Spns.

  • Reza Dastvan
  • , Ali Rasouli
  •  & Emad Tajkhorshid

• Article
  01 September 2022 | Open Access

  Percolation transition prescribes protein size-specific barrier to passive transport through the nuclear pore complex

  Combining realistic coarse-grained simulations with a percolation transition theory, this study elucidates the microscopic mechanism that governs the selectivity of passive, unassisted transport through the nuclear pore complex.

  • David Winogradoff
  • , Han-Yi Chou
  •  & Aleksei Aksimentiev

• Article
  16 August 2022 | Open Access

  ABCA1 is an extracellular phospholipid translocase

  ATP-binding cassette transporter A1 (ABCA1) drives phospholipid (PL) from the plasma membrane into extracellular apolipoprotein A-I, for the production of high density lipoprotein (HDL). Here, the authors use simulations to assess the mechanism of ABCA1 function and show that ABCA1 extracts lipid from the outer face of the plasma membrane.

  • Jere P. Segrest
  • , Chongren Tang
  •  & Jay W. Heinecke

• Article
  28 July 2022 | Open Access

  Protein shape sampled by ion mobility mass spectrometry consistently improves protein structure prediction

  Collision cross sections (CCS) from ion mobility mass spectrometry provide information about protein shape and size. Here, the authors develop an algorithm to predict CCS and integrate experimental ion mobility data into Rosetta-based molecular modelling to predict protein structures from sequence.

  • SM Bargeen Alam Turzo
  • , Justin T. Seffernick
  •  & Steffen Lindert