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| Open AccessGENESIS CGDYN: large-scale coarse-grained MD simulation with dynamic load balancing for heterogeneous biomolecular systems
Here, the authors report the development of heterogeneous domain decomposition with load balancing for large biological molecular dynamics simulations using residue-level coarse-grained models.
- Jaewoon Jung
- , Cheng Tan
- & Yuji Sugita
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Article
| Open AccessTertiary structure and conformational dynamics of the anti-amyloidogenic chaperone DNAJB6b at atomistic resolution
Adupa et al show how the anti-amyloidogenic molecular chaperone DNAJB6 adopts three conformational states that determine the accessibility of its substrate binding domain. In all states, interactions with HSP70 are shielded, suggesting that functional interactions only may occur upon substrate binding.
- Vasista Adupa
- , Elizaveta Ustyantseva
- & Patrick R. Onck
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Article
| Open AccessFunctional protein dynamics in a crystal
Work by Klyshko and Kim et al. lays the foundation for simulating pump-probe experiments and demonstrates how the dynamic behaviour of proteins extends to the crystal environment, emphasizing the need for an ensemble view in understanding functional motions.
- Eugene Klyshko
- , Justin Sung-Ho Kim
- & Sarah Rauscher
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| Open AccessKinetic trapping organizes actin filaments within liquid-like protein droplets
Here the authors perform modelling to reveal that the timescale of actin-VASP interactions plays a critical role in actin ring formation and filament length determines droplet deformation in VASP droplets: predictions from the model were tested against VASP GAB mutant.
- Aravind Chandrasekaran
- , Kristin Graham
- & Padmini Rangamani
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Article
| Open AccessHairpin trimer transition state of amyloid fibril
Amyloid fibrils are ordered protein assemblies implicated in neurodegenerative disease. Here the authors show that hairpin trimers can be transition states of fibril nucleation, explaining how different fibril isoforms may arise from alternative nucleation sites.
- Levent Sari
- , Sofia Bali
- & Milo M. Lin
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| Open AccessHigh-throughput prediction of protein conformational distributions with subsampled AlphaFold2
Protein dynamics, crucial for life, are difficult and expensive to predict. This study shows that AI-based structure prediction methods can be modified for rapidly predicting the conformational landscapes of proteins, with strong correlations with experimentally-measured relative state populations.
- Gabriel Monteiro da Silva
- , Jennifer Y. Cui
- & Brenda M. Rubenstein
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Article
| Open AccessA three-level regulatory mechanism of the aldo-keto reductase subfamily AKR12D
Here, the authors characterise an aldo-keto reductase AKRtyl, which belongs to a previously unidentified subfamily AKR12D. They uncover a complex mechanism of allosteric regulation that is mediated by 3 distinct states.
- Zhihong Xiao
- , Jinyin Zha
- & Shaobo Dai
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Article
| Open AccessSequence-dependent material properties of biomolecular condensates and their relation to dilute phase conformations
How material properties affect the functional state of biocondensates is a long-standing question. Here the authors demonstrate how such properties are encoded in a disordered protein sequence and can be predicted from dilute phase conformations.
- Dinesh Sundaravadivelu Devarajan
- , Jiahui Wang
- & Jeetain Mittal
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| Open AccessA druggable conformational switch in the c-MYC transactivation domain
Here, the authors identify a conformational switch in the amino-terminal transactivation domain of c-MYC, termed coreMYC, which cycles between a closed, inactive state and an open, active conformation. Polyphenol epigallocatechin gallate (EGCG) is used to modulate the conformational landscape of coreMYC, stabilizing the closed and inactive conformation.
- Dilraj Lama
- , Thibault Vosselman
- & Marie Arsenian Henriksson
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Article
| Open AccessFunctional regulation of aquaporin dynamics by lipid bilayer composition
Membrane proteins depend on their lipid environments. Using aquaporin as a model, the authors show that the choice of lipid bilayer fundamentally affects membrane protein structure, thermodynamics, kinetic, and function, even to the point of lipid-based inhibition.
- Anh T. P. Nguyen
- , Austin T. Weigle
- & Diwakar Shukla
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Article
| Open AccessDynamics of activation in the voltage-sensing domain of Ciona intestinalis phosphatase Ci-VSP
Understanding the molecular basis of voltage-sensing is of great importance in biology. Here, the authors use computational analysis and simulations to reveal atomic level insights into the mechanism of an isolated voltage-sensing domain.
- Spencer C. Guo
- , Rong Shen
- & Aaron R. Dinner
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| Open AccessDisordered regions in proteusin peptides guide post-translational modification by a flavin-dependent RiPP brominase
Here the authors use NMR, SAXS and MD simulations to characterise the structure of proteusin peptides, which are atypically long RiPP substrates. They show a small, unstructured region in the proteusin leader is sufficient for its interaction with a halogenase that brominates the terminal tryptophan residue.
- Nguyet A. Nguyen
- , F. N. U. Vidya
- & Vinayak Agarwal
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| Open AccessMesoscale simulation of biomembranes with FreeDTS
In this work, the authors report the FreeDTS software to simulate biomembranes at the mesoscale. The software provides various membrane simulations, focusing on protein organization and shape remodeling. A versatile tool propelling realistic membrane studies and diverse applications.
- Weria Pezeshkian
- & John H. Ipsen
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| Open AccessCryo-EM structure and B-factor refinement with ensemble representation
Cryo-EM is the go-to method for visualizing large, flexible biomolecules. Here, authors introduce a new Gaussian mixture modelling method for cryo-EM modelling tasks, including refinement, composite map generation and ensemble representation.
- Joseph G. Beton
- , Thomas Mulvaney
- & Maya Topf
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Article
| Open AccessLipid nanodisc scaffold and size alter the structure of a pentameric ligand-gated ion channel
The authors show that lipid nanodiscs of different scaffold type and size alter the structure of the pentameric ligand-gated ion channel, ELIC. The results suggest that nanodisc selection is an important consideration for structural studies of membrane proteins.
- Vikram Dalal
- , Mark J. Arcario
- & Wayland W. L. Cheng
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Article
| Open AccessExperimental determination and mathematical modeling of standard shapes of forming autophagosomes
Autophagosome formation involves membrane morphological changes. Here, authors statistically determined average shapes of forming autophagosomes from 3D electron micrographs and established a theoretical model that quantitatively reproduces them.
- Yuji Sakai
- , Satoru Takahashi
- & Noboru Mizushima
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Article
| Open AccessLocal energetic frustration conservation in protein families and superfamilies
Energetic local frustration in proteins may have been positively selected by evolution when related to function such as ligand binding, allostery and other. Here the authors present a methodology to analyze local frustration patterns within protein families and superfamilies.
- Maria I. Freiberger
- , Victoria Ruiz-Serra
- & Alfonso Valencia
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Article
| Open AccessMolecular basis and cellular functions of vinculin-actin directional catch bonding
This study provides insights into the directional catch bonding of the linker protein vinculin by elucidating the molecular basis of mechanical reinforcement as well as unveiling its key role in subcellular organization and cellular processes.
- Venkat R. Chirasani
- , Mohammad Ashhar I. Khan
- & Sharon L. Campbell
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Article
| Open AccessNonuniversal impact of cholesterol on membranes mobility, curvature sensing and elasticity
Cholesterol both thickens and condenses membranes, yet it also softens them under certain conditions. Here, authors uncover cholesterol’s dual role in the delicate balance of rigidity and flexibility in membranes, crucial for diverse biological functions.
- Matthias Pöhnl
- , Marius F. W. Trollmann
- & Rainer A. Böckmann
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| Open AccessA minority of final stacks yields superior amplitude in single-particle cryo-EM
Here the authors develop an iterative particle sieving method called CryoSieve, demonstrating this method outperforms other cryo-EM particle sorting algorithms to reveal that most particles are unnecessary in final stacks.
- Jianying Zhu
- , Qi Zhang
- & Chenglong Bao
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| Open AccessStructural and thermodynamic insights into antibody light chain tetramer formation through 3D domain swapping
Atomic-level structural examinations of antibody light chain aggregates are sparse. Here, the authors find an antibody light chain that maintains an equilibrium between monomeric and tetrameric states and show with its 3D structure that it engages in 3D domain swapping within its variable region.
- Takahiro Sakai
- , Tsuyoshi Mashima
- & Shun Hirota
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| Open AccessEnvironmental modulation of global epistasis in a drug resistance fitness landscape
Global epistasis can be used to reconstruct fitness landscapes and infer adaptive trajectories. Here, the authors investigate how environmental variation impacts patterns of global epistasis, finding that global epistasis in the malaria parasite P. falciparum can be modulated by drug concentration in the environment.
- Juan Diaz-Colunga
- , Alvaro Sanchez
- & C. Brandon Ogbunugafor
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Article
| Open AccessDynamical control enables the formation of demixed biomolecular condensates
In this work, the authors report that protein-RNA condensates with shared proteins and distinct RNAs can form and persist in vitro and in cells as distinct entities if the nonshared RNA molecules are dynamically arrested, but the shared protein components are dynamically exchangeable.
- Andrew Z. Lin
- , Kiersten M. Ruff
- & Rohit V. Pappu
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| Open AccessQuantification of ligand and mutation-induced bias in EGFR phosphorylation in direct response to ligand binding
The authors show that the oncogenic L834R EGFR mutation induces bias in EGFR signal transduction across the plasma membrane. While EGFR signalling is biased toward Y1068 phosphorylation, the mutation switches the preference to Y1173 phosphorylation.
- Daniel Wirth
- , Ece Özdemir
- & Kalina Hristova
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Article
| Open AccessMyr-Arf1 conformational flexibility at the membrane surface sheds light on the interactions with ArfGAP ASAP1
An integrated approach combing solution and solid-state NMR, molecular dynamics simulations and neutron reflectometry is applied to characterize dynamic membrane bound forms of ADP-ribosylation factor 1 (Arf1).
- Yue Zhang
- , Olivier Soubias
- & R. Andrew Byrd
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Article
| Open AccessPatterning and dynamics of membrane adhesion under hydraulic stress
Hydraulic fracturing remodels cell-cell adhesions in physiology and during development. Here, authors combine vesicle experiments and computational modeling to identify the physical principles behind biological fracking.
- Céline Dinet
- , Alejandro Torres-Sánchez
- & Margarita Staykova
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Article
| Open AccessSimulation-guided engineering of split GFPs with efficient β-strand photodissociation
Green fluorescent proteins (GFPs) are ubiquitous for protein tagging and live cell imaging. Here, authors have used computational methods to engineer a fast-dissociating split GFP, which could be used to study macromolecular interactions.
- Yasmin Shamsudin
- , Alice R. Walker
- & Steven G. Boxer
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Article
| Open AccessStructural insights into the modulation of coronavirus spike tilting and infectivity by hinge glycans
In this work, the authors combine cryo-electron tomography of vitrified virions, mass spectrometry, modeling, molecular dynamics and infectivity assay and report that a hinge glycan on viral spike protein influences virus infection and immune evasion.
- David Chmielewski
- , Eric A. Wilson
- & Wah Chiu
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| Open AccessAccurate prediction of protein folding mechanisms by simple structure-based statistical mechanical models
Predicting how proteins fold into specific native structures remains challenging. Here, the authors develop a simple physical model that accurately predicts protein folding mechanisms, paving the way for solving the folding process component of the protein folding problem.
- Koji Ooka
- & Munehito Arai
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Article
| Open AccessStructural basis of dimerization of chemokine receptors CCR5 and CXCR4
Here, authors report chemokine receptors structures obtained using coarse-grained metadynamics. CCR5 and CXCR4 homo- and heterodimers differ in the conformations of ligand binding sites and of the G protein interaction interface, suggesting structural basis for the rational design of biased ligands.
- Daniele Di Marino
- , Paolo Conflitti
- & Vittorio Limongelli
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| Open AccessChemo-mechanical forces modulate the topology dynamics of mesoscale DNA assemblies
Understanding the topological arrangement and transition dynamics of mesoscale assemblies is complicated by their molecular complexity. Here, the authors use DNA origami nanosprings to show that mesoscale helical handedness is dictated by backbone torque rather than achiral orientation.
- Deepak Karna
- , Eriko Mano
- & Hanbin Mao
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Article
| Open AccessLptM promotes oxidative maturation of the lipopolysaccharide translocon by substrate binding mimicry
Here, the authors identify a third component of the outer membrane LPS translocon in Escherichia coli called LptM. Biochemical analysis and structural modelling reveal that LptM binds the LPS translocon by mimicking its native substrate, so stabilising an active conformation of the complex.
- Yiying Yang
- , Haoxiang Chen
- & Raffaele Ieva
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Article
| Open AccessDetermining subunit-subunit interaction from statistics of cryo-EM images: observation of nearest-neighbor coupling in a circadian clock protein complex
Deciphering interactions between subunits in protein complexes is an important problem. By combining cryo-EM imaging and statistical modeling, Han and colleagues reveal a significant cooperativity between subunits in the clock protein hexamer KaiC.
- Xu Han
- , Dongliang Zhang
- & Qi Ouyang
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Article
| Open AccessThermodynamic forces from protein and water govern condensate formation of an intrinsically disordered protein domain
In this work, the authors report atomistic molecular dynamics simulations showing that solvation entropy and protein-protein interactions are the main thermodynamic driving forces for the formation of condensates of the intrinsically disordered domain of the protein FUS.
- Saumyak Mukherjee
- & Lars V. Schäfer
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Article
| Open AccessSelf-organized and directed branching results in optimal coverage in developing dermal lymphatic networks
The lymphatic system is a transport network that controls immune response and tissue fluid circulation in the body. Here the authors combine experiment and theory to reveal that developing lymphatic capillary networks exploit complementary branching strategies to optimize tissue coverage.
- Mehmet Can Uçar
- , Edouard Hannezo
- & Kari Vaahtomeri
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| Open AccessElevated concentrations cause upright alpha-synuclein conformation at lipid interfaces
The misfolding of alpha-synuclein is associated with neurodegenerative disorders such as Parkinson’s disease. The authors report a mechanism explaining why lipid membranes catalyze the formation of harmful aggregates at elevated concentrations.
- Steven J. Roeters
- , Kris Strunge
- & Tobias Weidner
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| Open AccessThe H163A mutation unravels an oxidized conformation of the SARS-CoV-2 main protease
SARS-CoV-2 main protease adapts a disulfide bonded inactive state to escape oxidative stress. Here, the authors report a crystal structure of an inactive conformation of the enzyme achieved through a H163A mutation, and the mechanistic details of conformational changes using atomistic simulations.
- Norman Tran
- , Sathish Dasari
- & Aravindhan Ganesan
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| Open AccessGeometric alignment of aminoacyl-tRNA relative to catalytic centers of the ribosome underpins accurate mRNA decoding
Protein synthesis is dependent on the ribosome’s ability to accurately select tRNA. Molecular simulations reveal divergent pathways for correct and incorrect tRNA during selection, indicating that tRNA alignment is key to protein production.
- Dylan Girodat
- , Hans-Joachim Wieden
- & Karissa Y. Sanbonmatsu
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Article
| Open AccessMolecular architecture and conservation of an immature human endogenous retrovirus
The hexagonal immature capsid lattice of human endogenous retrovirus K is determined at 3.2 Å resolution, which is an assembly of small molecule-stabilized hexamers via dimer and trimer interfaces, a highly conserved mechanism among retroviruses.
- Anna-Sophia Krebs
- , Hsuan-Fu Liu
- & Peijun Zhang
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| Open AccessThe net electrostatic potential and hydration of ABCG2 affect substrate transport
ABCG2, an ATP-binding cassette transporter, extrudes hundreds of hydrophilic and hydrophobic compounds from cells, playing roles in xenobiotic clearance or multidrug resistance in cancer. Gose et al provide key insights into ABCG2 substrate selection.
- Tomoka Gose
- , Heather M. Aitken
- & John D. Schuetz
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| Open AccessCrystal structures of MHC class I complexes reveal the elusive intermediate conformations explored during peptide editing
The unusual crystal structures of MHC I-peptide complexes provide a visualization of the remarkable ability of the groove to adapt conformationally to bound peptides, explaining how MHC I molecules edit peptides in antigen presentation.
- Lenong Li
- , Xubiao Peng
- & Marlene Bouvier
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| Open AccessMembrane mediated mechanical stimuli produces distinct active-like states in the AT1 receptor
The AT1 GPCR plays an essential role in cardiovascular regulation and may be activated by the peptide AngII as well as membrane stretch. Here, Poudel et al. use molecular simulations to show that membrane-mediated activation produces distinct active-like conformations when compared to activation by AngII.
- Bharat Poudel
- , Rajitha Rajeshwar T
- & Juan M. Vanegas
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Article
| Open AccessPartition complex structure can arise from sliding and bridging of ParB dimers
In many bacteria and plasmids, DNA segregation is controlled by the ParABS system, an essential component of which is the formation of a nucleoprotein complex. Here, making use of recent discoveries, the authors develop a sliding and bridging model to predict the fine structure of this complex.
- Lara Connolley
- , Lucas Schnabel
- & Seán M. Murray
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Article
| Open AccessGPCRome-wide analysis of G-protein-coupling diversity using a computational biology approach
Selective GPCR-G protein complexes formation is critical for signal transduction regulation. Here, the authors use a data-driven approach to show that the structures of experimental and predicted complex interfaces inform, at least partially, on G protein binding preferences.
- Marin Matic
- , Pasquale Miglionico
- & Francesco Raimondi
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Article
| Open AccessAllosteric activation of vinculin by talin
Vinculin binding to talin is a key event in focal adhesion dynamics; yet, how vinculin is activated to recruit actin remains unknown. Here, the authors use a multiscale approach to reveal that talin activates vinculin through an intricate allosteric mechanism tightly regulated by force.
- Florian Franz
- , Rafael Tapia-Rojo
- & Frauke Gräter
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Article
| Open AccessThe structural basis of divalent cation block in a tetrameric prokaryotic sodium channel
Divalent cation block is observed in various tetrameric ion channels. Here, authors use X-ray crystallography, electrophysiology and molecular dynamics simulations to reveal the mechanism of the divalent cation block on a prokaryotic sodium channel.
- Katsumasa Irie
- , Yoshinori Oda
- & Yoshinori Fujiyoshi
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Article
| Open AccessDiscovering functionally important sites in proteins
An important step in understanding and using proteins is to identify the residues that are important for function. The authors present a machine-learning based method to predict functional sites that leverages and combines the information available in protein sequences and structures.
- Matteo Cagiada
- , Sandro Bottaro
- & Kresten Lindorff-Larsen
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Article
| Open AccessPredicting scale-dependent chromatin polymer properties from systematic coarse-graining
Here the authors provide a quantitative description of chromatin as bead-spring polymers. The study predicts the 3D size of chromatin beads given the genomic length and computes how stretchable and bendable chromatin is and how soft chromatin beads are.
- Sangram Kadam
- , Kiran Kumari
- & Ranjith Padinhateeri
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Article
| Open AccessMutagenesis and structural studies reveal the basis for the specific binding of SARS-CoV-2 SL3 RNA element with human TIA1 protein
Here the authors reveal the binding interface for the SARS-CoV-2 SL3 RNA element to human TIA1 protein and find that disruptions of the identified viral RNA-host protein interactions with designed ASOs reduce SARS-CoV-2 infection in cells.
- Dong Zhang
- , Lulu Qiao
- & Ruhong Zhou