Featured
-
-
Article
| Open Access
Exposing the molecular heterogeneity of glycosylated biotherapeutics
The molecular heterogeneity of glycosylated biotherapeutics often complicates analysis by intact mass spectrometry. Here, the authors propose a simplified procedure for characterization that employs proton transfer charge reduction. Integration with glycomic and glycopeptide datasets can further provide glycoform-level information.
- Luis F. Schachner
- , Christopher Mullen
- & Wendy Sandoval
-
Article
| Open Access
Cryo-EM structures of prokaryotic ligand-gated ion channel GLIC provide insights into gating in a lipid environment
Gloeobacter proton-gated ion channel (GLIC) is a convenient model of pentameric ligand-gated ion channels. Here, Bharambe & Li et al. report structures and simulations of GLIC with insights into the role of lipids in GLIC gating mechanism.
- Nikhil Bharambe
- , Zhuowen Li
- & Sandip Basak
-
Article
| Open Access
Correlating fluorescence microscopy, optical and magnetic tweezers to study single chiral biopolymers such as DNA
It is hard to correlate force, torque and localization information. The authors report Combined Optical and Magnetic BIomolecule TWEEZers, COMBI-Tweez, that integrates optical trapping, time-resolved electromagnetic tweezers, and fluorescence microscopy: they demonstrate visualisation of higher order structural motifs in DNA.
- Jack W. Shepherd
- , Sebastien Guilbaud
- & Mark C. Leake
-
Article
| Open Access
3D molecular generative framework for interaction-guided drug design
Designing a molecule that favorably binds to a protein pocket is a keystone of drug discovery. Zhung et al. devise DeepICL, which leverages the generalizable features of non-covalent protein-ligand interactions on a 3D molecular generative model, improving the quality of AI-designed molecules.
- Wonho Zhung
- , Hyeongwoo Kim
- & Woo Youn Kim
-
Article
| Open Access
Functional 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
-
Article
| Open Access
An alpha-helical lid guides the target DNA toward catalysis in CRISPR-Cas12a
CRISPR-Cas12a is a powerful RNA-guided genome-editing system. Saha et al. show that an alpha-helical lid plays the central role in guiding the target DNA toward the single RuvC nuclease domain, resulting in a double-stranded DNA break.
- Aakash Saha
- , Mohd Ahsan
- & Giulia Palermo
-
Article
| Open Access
Ligand coupling mechanism of the human serotonin transporter differentiates substrates from inhibitors
The serotonin transporter, targeted by several medications, terminates neurotransmission by clearing serotonin from the synaptic cleft. Combining biochemical results with in silico data, the authors show the key interactions that initiate substrate transport.
- Ralph Gradisch
- , Katharina Schlögl
- & Thomas Stockner
-
Article
| Open Access
Enhancing geometric representations for molecules with equivariant vector-scalar interactive message passing
Utilising geometric information and reducing computational costs are key challenges in the molecular modelling field. Here, authors propose ViSNet, which efficiently extracts geometric features, accurately predicts molecular properties, and drives simulations with interpretability.
- Yusong Wang
- , Tong Wang
- & Tie-Yan Liu
-
Article
| Open Access
Competition between inside-out unfolding and pathogenic aggregation in an amyloid-forming β-propeller
Here, the relationship between unfolding and amyloid aggregation of glaucoma-associated myocilin is probed, showing that myocilin is not at equilibrium and pathogenic aggregation competes directly with unfolding.
- Emily G. Saccuzzo
- , Mubark D. Mebrat
- & Raquel L. Lieberman
-
Article
| Open Access
Merizo: a rapid and accurate protein domain segmentation method using invariant point attention
Proteins contain modular structural and functional units called domains. Here, the authors have developed Merizo, a deep learning method for domain segmentation applicable to experimental structures as well as those generated by AlphaFold2.
- Andy M. Lau
- , Shaun M. Kandathil
- & David T. Jones
-
Article
| Open Access
Molecular 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
-
Article
| Open Access
Understanding the molecular mechanisms of odorant binding and activation of the human OR52 family
Limited insight existed on human odorant receptors (ORs). Here, the authors present structures of consensus OR52 in its inactive and active forms, shedding light on the activation mechanism of the OR52 family.
- Chulwon Choi
- , Jungnam Bae
- & Hee-Jung Choi
-
Article
| Open Access
LipIDens: simulation assisted interpretation of lipid densities in cryo-EM structures of membrane proteins
Interpretation of lipid-like densities in cryo-EM structures of membrane proteins is challenging. Here authors present LipIDens, enabling molecular dynamics analysis of protein-lipid interactions.
- T. Bertie Ansell
- , Wanling Song
- & Mark S. P. Sansom
-
Article
| Open Access
ProRefiner: an entropy-based refining strategy for inverse protein folding with global graph attention
Inverse Protein Folding is a critical component of protein design. Here, authors introduce ProRefiner, a deep-learning model for IPF that exhibits both high performance and memory efficiency, thereby contributing to advancements in protein design.
- Xinyi Zhou
- , Guangyong Chen
- & Pheng Ann Heng
-
Article
| Open Access
trRosettaRNA: automated prediction of RNA 3D structure with transformer network
Here, authors develop trRosettaRNA, a deep learning-based approach for predicting RNA 3D structures. Blind tests demonstrate that the automated predictions compete effectively with top human predictions on natural RNAs.
- Wenkai Wang
- , Chenjie Feng
- & Jianyi Yang
-
Article
| Open Access
Structural 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
-
Article
| Open Access
Elevator-like movements of prestin mediate outer hair cell electromotility
Probing the molecular dynamics of the membrane motor, prestin, with biophysical measures and MD simulations, Kuwabara et al. find that an elevator-like domain movement across the membrane produces the unique piezoelectric behavior.
- Makoto F. Kuwabara
- , Bassam G. Haddad
- & Dominik Oliver
-
Article
| Open Access
De novo design of knotted tandem repeat proteins
This study reports the successful de novo design of a trefoil knotted protein fold for which the crystal structure agrees closely with the intended trefoil knot topology.
- Lindsey A. Doyle
- , Brittany Takushi
- & Philip Bradley
-
Article
| Open Access
Distantly related Alteromonas bacteriophages share tail fibers exhibiting properties of transient chaperone caps
Receptor binding proteins in bacteriophage tails mediate host recognition and thus infectivity. Here Gonzalez et al. identify a receptor binding module shared by different phages that all use receptor binding tail fibers that are transiently capped by their chaperones.
- Rafael Gonzalez-Serrano
- , Riccardo Rosselli
- & Matthew Dunne
-
Article
| Open Access
HLA3DB: comprehensive annotation of peptide/HLA complexes enables blind structure prediction of T cell epitopes
Structure prediction of peptide/HLA (pHLA) complexes has been mired by the inability to accurately model the middle of the peptide. Here, the authors present a curated database of pHLA structures (HLA3DB) and identify discrete peptide backbone conformations that are used for high fidelity modelling.
- Sagar Gupta
- , Santrupti Nerli
- & Nikolaos G. Sgourakis
-
Article
| Open Access
Claudin-23 reshapes epithelial tight junction architecture to regulate barrier function
Claudin family proteins are important for regulating epithelial barrier function. Here the authors show that claudin-23 controls paracellular flux by combining with other claudins to alter tight junction architecture and permeability.
- Arturo Raya-Sandino
- , Kristen M. Lozada-Soto
- & Asma Nusrat
-
Article
| Open Access
Thermodynamic 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
-
Article
| Open Access
Organisation of the orthobunyavirus tripodal spike and the structural changes induced by low pH and K+ during entry
Enveloped viruses employ the maturing environment of endosomes to promote endosomal escape. Here, authors generate a pseudo-atomic model of the BUNV envelope using sub-tomogram averaging and AlphaFold, and identify ionic cues for fusion events.
- Samantha Hover
- , Frank W. Charlton
- & Juan Fontana
-
Article
| Open Access
Discovery and pharmacophoric characterization of chemokine network inhibitors using phage-display, saturation mutagenesis and computational modelling
Ticks inject evasins at the bite site to bind multiple redundant chemokines and inhibit inflammation allowing blood feeding. Here, the authors identify evasin derived short peptides with broad spectrum anti-chemokine activity that could be used to develop new treatments for inflammatory disease.
- Serena Vales
- , Jhanna Kryukova
- & Shoumo Bhattacharya
-
Article
| Open Access
Machine learning coarse-grained potentials of protein thermodynamics
Understanding protein dynamics is a complex scientific challenge. Here, authors construct coarse-grained molecular potentials using artificial neural networks, significantly accelerating protein dynamics simulations while preserving their thermodynamics.
- Maciej Majewski
- , Adrià Pérez
- & Gianni De Fabritiis
-
Article
| Open Access
Molecular basis of TASL recruitment by the peptide/histidine transporter 1, PHT1
The peptide/histidine transporter 1, PHT1 (SLC15A4), is required for TLR-IRF5 activation via the adaptor protein TASL. Here, the authors determined the structure of PHT1 in the outward-open conformation and present a model of the PHT1-TASL complex where the first 16 residues of TASL bind into the central cavity of PHT1.
- Tânia F. Custódio
- , Maxime Killer
- & Christian Löw
-
Article
| Open Access
A strategy for Cas13 miniaturization based on the structure and AlphaFold
Small Cas enzymes are required for therapeutic use. Here the authors report an Interaction, Dynamics and Conservation (IDC) strategy for protein miniaturisation and use this to generate five compact variants of Cas13 based on a combination of IDC strategy and AlphaFold2.
- Feiyu Zhao
- , Tao Zhang
- & Zhanjun Li
-
Article
| Open Access
Fluorescent protein lifetimes report densities and phases of nuclear condensates during embryonic stem-cell differentiation
Fluorescent proteins can report on many cellular variables. Here, authors develop a method for reporting high local densities, and use it to show that density distribution of heterochromatin in mouse embryonic stem cells are not in a liquid phase.
- Khalil Joron
- , Juliane Oliveira Viegas
- & Eitan Lerner
-
Article
| Open Access
Structural and functional fine mapping of cysteines in mammalian glutaredoxin reveal their differential oxidation susceptibility
Glutaredoxin (GLRX) is a key enzyme in redox regulation via oxidation of protein cysteines and its activity is disrupted in diverse human diseases. This study integrates molecular modeling and biochemical validation to provide insights into the mechanisms of oxidative inactivation of GLRX.
- Elizabeth M. Corteselli
- , Mona Sharafi
- & Yvonne M. W. Janssen-Heininger
-
Article
| Open Access
Ion selectivity and rotor coupling of the Vibrio flagellar sodium-driven stator unit
In this work, the authors provide mechanistic insights for understanding the sodium-dependent, bacterial flagellar stator unit PomAB ion selectivity, directional rotation, and rotor incorporation in Vibrio spp.
- Haidai Hu
- , Philipp F. Popp
- & Nicholas M. I. Taylor
-
Article
| Open Access
GPCRome-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
-
Article
| Open Access
Targeting an allosteric site in dynamin-related protein 1 to inhibit Fis1-mediated mitochondrial dysfunction
Dynamin-related protein 1 (Drp1) mediates physiological and pathological mitochondrial fission, and the latter can be selectively blocked by a peptide inhibitor. Here, the authors identify a small molecule that mimics the benefits of this peptide inhibitor in cells and a mouse model of endotoxemia.
- Luis Rios
- , Suman Pokhrel
- & Daria Mochly-Rosen
-
Article
| Open Access
Conformational restriction shapes the inhibition of a multidrug efflux adaptor protein
Multidrug efflux protein pumps are key players in bacterial antimicrobial resistance. Here, the authors show how dynamics of a periplasmic pump component can be targeted for efflux inhibition.
- Benjamin Russell Lewis
- , Muhammad R. Uddin
- & Eamonn Reading
-
Article
| Open Access
pH-dependence of the Plasmodium falciparum chloroquine resistance transporter is linked to the transport cycle
PfCRT is a chloroquine resistance transporter from malaria parasite Plasmodium falciparum, which is sensitive to acidic pH. Here, the authors show that residue E207 is critical for pH sensing by PfCRT, using alanine-scanning mutagenesis, MD simulations and drug uptake assays.
- Fiona Berger
- , Guillermo M. Gomez
- & Michael Lanzer
-
Article
| Open Access
Molecular mechanism of phosphopeptide neoantigen immunogenicity
Phosphorylated peptide antigens are present on cancer cells, but their role in cancer immunity is unknown. Here, the authors describe a molecular mechanism, by which a tumor-specific phosphopeptide found in acute myeloid leukemia is recognized by the human immune T cells.
- Yury Patskovsky
- , Aswin Natarajan
- & Michelle Krogsgaard
-
Article
| Open Access
Cyclic di-AMP traps proton-coupled K+ transporters of the KUP family in an inward-occluded conformation
Second messengers regulate a broad spectrum of processes in bacteria. Here, authors characterize how the second messenger cyclic di-AMP inhibits the potassium transporter KimA using cryo-EM, molecular dynamics simulations and functional assays.
- Michael F. Fuss
- , Jan-Philip Wieferig
- & Inga Hänelt
-
Article
| Open Access
A multicentric consortium study demonstrates that dimethylarginine dimethylaminohydrolase 2 is not a dimethylarginine dimethylaminohydrolase
While dimethylarginine dimethylaminohydrolase 1 (DDAH1) is known to metabolize the endogenous inhibitor of nitric oxide synthases, asymmetric dimethylarginine (ADMA), the function of DDAH2 has remained controversial. Here, the authors present several lines of evidence that DDAH2 does not hydrolyze ADMA.
- Vinitha N. Ragavan
- , Pramod C. Nair
- & Roman N. Rodionov
-
Article
| 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
| Open Access
Computational design of dynamic receptor—peptide signaling complexes applied to chemotaxis
Engineering protein biosensors that respond to biomolecules by triggering cellular responses has largely relied on binding rigid molecules. Here, the authors develop a computational strategy for designing signaling complexes between conformationally dynamic proteins and peptides.
- Robert E. Jefferson
- , Aurélien Oggier
- & Patrick Barth
-
Article
| Open Access
Structural analysis and architectural principles of the bacterial amyloid curli
Using Alpha fold modelling and cryo-EM reconstruction the authors reveal the structural and architectural principles of the bacterial functional amyloid curli, encompassing the continuous stacking of β-solenoid pseudo repeats within and across subunits.
- Mike Sleutel
- , Brajabandhu Pradhan
- & Han Remaut
-
Article
| Open Access
Metal3D: a general deep learning framework for accurate metal ion location prediction in proteins
Zinc is an essential metal for many proteins. Here, the authors propose a model based on 3D convolutional networks to predict the location of zinc in experimental and computationally predicted structures within a framework readily extensible to other metals.
- Simon L. Dürr
- , Andrea Levy
- & Ursula Rothlisberger
-
Article
| Open Access
Sequence-structure-function relationships in the microbial protein universe
Advances in protein structure prediction have led to a significant influx of protein structure data. Here the authors exploit this data to offer an unbiased overview of complex sequence-structure-function relationships in the protein universe. This work opens up new uses for 3D structure data repositories in meta-omics and other fields of biology.
- Julia Koehler Leman
- , Pawel Szczerbiak
- & Tomasz Kosciolek
-
Article
| Open Access
Dual domain recognition determines SARS-CoV-2 PLpro selectivity for human ISG15 and K48-linked di-ubiquitin
Understanding mechanisms of PLpro substrate selectivity offers new ways to decouple substrate activities and will inform new therapeutic strategies. Here, the authors use multi-disciplinary approaches to uncover how PLpro from SARS-CoV-2 can discriminate between different substrates.
- Pawel M. Wydorski
- , Jerzy Osipiuk
- & Lukasz A. Joachimiak
-
Article
| Open Access
Fast, accurate antibody structure prediction from deep learning on massive set of natural antibodies
Prediction of antibody structures is critical for understanding and designing novel therapeutic and diagnostic molecules. Here, the authors present IgFold: a fast, accurate method for antibody structure prediction using an end-to-end deep learning model.
- Jeffrey A. Ruffolo
- , Lee-Shin Chu
- & Jeffrey J. Gray
-
Article
| 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
| Open Access
PeSTo: parameter-free geometric deep learning for accurate prediction of protein binding interfaces
Predicting protein interactions is crucial for understanding biological functions. Here, authors introduce a geometric transformer that accurately identifies protein binding interfaces, enabling new insights into unexplored biology.
- Lucien F. Krapp
- , Luciano A. Abriata
- & Matteo Dal Peraro
-
Article
| 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
| Open Access
Improving the generalizability of protein-ligand binding predictions with AI-Bind
State-of-the-art machine learning models in drug discovery fail to reliably predict the binding properties of poorly annotated proteins and small molecules. Here, the authors present AI-Bind, a machine learning pipeline to improve generalizability and interpretability of binding predictions.
- Ayan Chatterjee
- , Robin Walters
- & Giulia Menichetti
-
Article
| Open Access
A Vaccinia-based system for directed evolution of GPCRs in mammalian cells
G protein-coupled receptors are a major class of drug targets. Here, the authors develop a method whereby their biophysical and functional properties can be altered through directed evolution in mammalian cells, leading to variants exhibiting features such as high stability and expression, or increased allosteric coupling.
- Christoph Klenk
- , Maria Scrivens
- & Andreas Plückthun
GENESIS CGDYN: large-scale coarse-grained MD simulation with dynamic load balancing for heterogeneous biomolecular systems