Accurate structure prediction of biomolecular interactions with AlphaFold 3

Nature, Journal Year: 2024, Volume and Issue: 630(8016), P. 493 - 500

Published: May 8, 2024

Abstract The introduction of AlphaFold 2 1 has spurred a revolution in modelling the structure proteins and their interactions, enabling huge range applications protein design 2–6 . Here we describe our 3 model with substantially updated diffusion-based architecture that is capable predicting joint complexes including proteins, nucleic acids, small molecules, ions modified residues. new demonstrates improved accuracy over many previous specialized tools: far greater for protein–ligand interactions compared state-of-the-art docking tools, much higher protein–nucleic acid nucleic-acid-specific predictors antibody–antigen prediction AlphaFold-Multimer v.2.3 7,8 Together, these results show high-accuracy across biomolecular space possible within single unified deep-learning framework.

Language: Английский

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AlphaFold Protein Structure Database in 2024: providing structure coverage for over 214 million protein sequences

Nucleic Acids Research, Journal Year: 2023, Volume and Issue: 52(D1), P. D368 - D375

Published: Nov. 2, 2023

The AlphaFold Database Protein Structure (AlphaFold DB, https://alphafold.ebi.ac.uk) has significantly impacted structural biology by amassing over 214 million predicted protein structures, expanding from the initial 300k structures released in 2021. Enabled groundbreaking AlphaFold2 artificial intelligence (AI) system, predictions archived DB have been integrated into primary data resources such as PDB, UniProt, Ensembl, InterPro and MobiDB. Our manuscript details subsequent enhancements archiving, covering successive releases encompassing model organisms, global health proteomes, Swiss-Prot integration, a host of curated datasets. We detail access mechanisms direct file via FTP to advanced queries using Google Cloud Public Datasets programmatic endpoints database. also discuss improvements services added since its release, including Predicted Aligned Error viewer, customisation options for 3D search engine DB.

Language: Английский

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Architecture of the cytoplasmic face of the nuclear pore

Science, Journal Year: 2022, Volume and Issue: 376(6598)

Published: June 9, 2022

INTRODUCTION The subcellular compartmentalization of eukaryotic cells requires selective transport folded proteins and protein-nucleic acid complexes. Embedded in nuclear envelope pores, which are generated by the circumscribed fusion inner outer membranes, pore complexes (NPCs) sole bidirectional gateways for nucleocytoplasmic transport. ~110-MDa human NPC is an ~1000-protein assembly that comprises multiple copies ~34 different proteins, collectively termed nucleoporins. symmetric core composed ring encircling central channel rings formed Y‑shaped coat nucleoporin (CNCs) anchored atop both sides envelope. decorated with compartment‑specific asymmetric basket cytoplasmic filament nucleoporins, establish directionality provide docking sites factors small guanosine triphosphatase Ran. nucleoporins also play essential role irreversible remodeling messenger ribonucleoprotein particles (mRNPs) as they exit channel. Unsurprisingly, NPC's face represents a hotspot disease‑associated mutations commonly targeted viral virulence factors. RATIONALE Previous studies established near-atomic composite structure combining (i) biochemical reconstitution to elucidate interaction network between (ii) crystal single-particle cryo-electron microscopy determination reveal their three-dimensional shape molecular details interactions, (iii) quantitative tomography (cryo-ET) maps intact uncover stoichiometry positioning, (iv) cell‑based assays validate physiological relevance structural findings. In this work, we extended our approach architecture NPC. RESULTS Using reconstitution, elucidated protein-protein protein-RNA networks Chaetomium thermophilum establishing evolutionarily conserved heterohexameric complex (CFNC) held together heterotrimeric coiled‑coil hub tethers two separate mRNP‑remodeling Further analysis series structures revealed metazoan‑specific NUP358 16 distinct domains, including N‑terminal S‑shaped α‑helical solenoid followed oligomerization element, numerous Ran‑interacting E3 ligase domain, C‑terminal prolyl‑isomerase domain. Physiologically validated into cryo-ET pentameric bundles, conjoined through domains stalk regions CNC, projecting flexibly attached far ~600 Å cytoplasm. assays, demonstrated dispensable architectural integrity assembled interphase RNA export but required efficient translation. After assignment, remaining 4-shaped cryo‑ET density matched dimensions CFNC hub, close proximity outer-ring NUP93. Whereas N-terminal NUP93 sensor motif anchors properly related heterotrimer ring, confirmed reused anchoring By contrast, C. CFNCs divergent mechanism involves sensors located unstructured portions CNC unassigned occupies binding on face, component ELYS equivalent position unoccupied, suggesting mechanisms other than steric competition promote distribution CONCLUSION We have substantially advanced characterization nucleoporins' attachment at faces Our near‑atomic provides framework elucidating basis mRNP remodeling, factor interference function, underlying diseases [Figure: see text].

Language: Английский

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AlphaPulldown—a python package for protein–protein interaction screens using AlphaFold-Multimer

Bioinformatics, Journal Year: 2022, Volume and Issue: 39(1)

Published: Nov. 21, 2022

The artificial intelligence-based structure prediction program AlphaFold-Multimer enabled structural modelling of protein complexes with unprecedented accuracy. Increasingly, is also used to discover new protein-protein interactions (PPIs). Here, we present AlphaPulldown, a Python package that streamlines PPI screens and high-throughput higher-order oligomers using AlphaFold-Multimer. It provides convenient command-line interface, variety confidence scores graphical analysis tool.AlphaPulldown freely available at https://www.embl-hamburg.de/AlphaPulldown.Supplementary note Bioinformatics online.

Language: Английский

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Can enterprise green technology innovation performance achieve “corner overtaking” by using artificial intelligence?—Evidence from Chinese manufacturing enterprises

Technological Forecasting and Social Change, Journal Year: 2023, Volume and Issue: 194, P. 122732 - 122732

Published: July 14, 2023

Language: Английский

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Molecular dynamics simulation of an entire cell

Frontiers in Chemistry, Journal Year: 2023, Volume and Issue: 11

Published: Jan. 18, 2023

The ultimate microscope, directed at a cell, would reveal the dynamics of all cell's components with atomic resolution. In contrast to their real-world counterparts, computational microscopes are currently on brink meeting this challenge. perspective, we show how an integrative approach can be employed model entire minimal JCVI-syn3A, full complexity. This step opens way interrogate spatio-temporal evolution molecular simulations, that extended other cell types in near future.

Language: Английский

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Architecture of the linker-scaffold in the nuclear pore

Science, Journal Year: 2022, Volume and Issue: 376(6598)

Published: June 9, 2022

INTRODUCTION In eukaryotic cells, the selective bidirectional transport of macromolecules between nucleus and cytoplasm occurs through nuclear pore complex (NPC). Embedded in envelope pores, ~110-MDa human NPC is an ~1200-Å-wide ~750-Å-tall assembly ~1000 proteins, collectively termed nucleoporins. Because NPC's eightfold rotational symmetry along nucleocytoplasmic axis, each ~34 different nucleoporins multiples eight. Architecturally, symmetric core composed inner ring encircling central channel two outer rings anchored on both sides envelope. its role flow genetic information from DNA to RNA protein, commonly targeted viral infections nucleoporin constituents are associated with a plethora diseases. RATIONALE Although arrangement most scaffold was determined by quantitative docking crystal structures into cryo-electron tomographic (cryo-ET) maps intact NPCs, topology molecular details their cohesion multivalent linker have remained elusive. Recently, situ cryo-ET reconstructions NPCs various species indicated that capable reversible constriction dilation response variations membrane tension, thereby modulating diameter ~200 Å. We combined biochemical reconstitution, high-resolution single-particle microscopy (cryo-EM) structure determination, maps, physiological validation elucidate architecture linker-scaffold interaction network not only essential for integrity but also confers plasticity robustness necessary allow withstand such large-scale conformational changes. RESULTS By biochemically mapping scaffold-binding regions all fungal determining cryo-EM complexes, we completed characterization tractable established evolutionary conservation, despite considerable sequence divergence. series Nup188 Nup192 hubs bound Nic96, Nup145N, Nup53 binding regions, revealing proteins form distinct question mark-shaped keystones evolutionarily conserved hetero‑octameric complexes. Linkers bind surface pockets short defined motifs, flanking forming additional disperse interactions reinforce binding. Using structure‑guided functional analysis

Language: Английский

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The impact of AlphaFold Protein Structure Database on the fields of life sciences

PROTEOMICS, Journal Year: 2022, Volume and Issue: 23(17)

Published: Nov. 16, 2022

Abstract Arguably, 2020 was the year of high‐accuracy protein structure predictions, with AlphaFold 2.0 achieving previously unseen accuracy in Critical Assessment Protein Structure Prediction (CASP). In 2021, DeepMind and EMBL‐EBI developed Database to make an unprecedented number reliable predictions easily accessible broad scientific community. We provide a brief overview describe latest developments database. highlight how fields data services, bioinformatics, structural biology, drug discovery are directly affected by influx data. also show examples cutting‐edge research that took advantage It is apparent connections between various through structures now possible, but amount poses new challenges. Finally, we give outlook regarding future direction database, both terms sets functionalities.

Language: Английский

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Bringing Structure to Cell Biology with Cryo-Electron Tomography

Annual Review of Biophysics, Journal Year: 2023, Volume and Issue: 52(1), P. 573 - 595

Published: May 9, 2023

Recent advances in cryo-electron microscopy have marked only the beginning of potential this technique. To bring structure into cell biology, modality tomography has fast developed a bona fide situ structural biology technique where structures are determined their native environment, cell. Nearly every step cryo-focused ion beam-assisted electron (cryo-FIB-ET) workflow been improved upon past decade, since first windows were carved cells, unveiling macromolecular networks near-native conditions. By bridging and cryo-FIB-ET is advancing our understanding structure–function relationships environment becoming tool for discovering new biology.

Language: Английский

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Visualizing the disordered nuclear transport machinery in situ

Nature, Journal Year: 2023, Volume and Issue: 617(7959), P. 162 - 169

Published: April 26, 2023

Abstract The approximately 120 MDa mammalian nuclear pore complex (NPC) acts as a gatekeeper for the transport between nucleus and cytosol 1 . central channel of NPC is filled with hundreds intrinsically disordered proteins (IDPs) called FG-nucleoporins (FG-NUPs) 2,3 Although structure scaffold has been resolved in remarkable detail, actual machinery built up by FG-NUPs—about 50 MDa—is depicted an 60-nm hole even highly tomograms and/or structures computed artificial intelligence 4–11 Here we directly probed conformations vital FG-NUP98 inside NPCs live cells permeabilized intact using synthetic biology-enabled site-specific small-molecule labelling approach paired time-resolved fluorescence microscopy. Single cell measurements distance distribution segments combined coarse-grained molecular simulations allowed us to map uncharted environment nanosized channel. We determined that provides—in terminology Flory polymer theory 12 —a ‘good solvent’ environment. This enables FG domain adopt expanded thus control cytoplasm. With more than 30% proteome being formed from IDPs, our study opens window into resolving disorder–function relationships IDPs situ, which are important various processes, such cellular signalling, phase separation, ageing viral entry.

Language: Английский

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