Updated resources for exploring experimentally-determined PDB structures and Computed Structure Models at the RCSB Protein Data Bank

Nucleic Acids Research, Год журнала: 2024, Номер 53(D1), С. D564 - D574

Опубликована: Ноя. 28, 2024

The Research Collaboratory for Structural Bioinformatics Protein Data Bank (RCSB PDB, RCSB.org), the US Worldwide (wwPDB, wwPDB.org) data center global PDB archive, provides access to via its RCSB.org research-focused web portal. We report substantial additions tools and visualization features available at RCSB.org, which now delivers more than 227000 experimentally determined atomic-level three-dimensional (3D) biostructures stored in archive alongside 1 million Computed Structure Models (CSMs) of proteins (including models human, model organisms, select human pathogens, crop plants organisms important addressing climate change). In addition providing support 3D structure motif searches with user-provided coordinates, new highlighted herein include query results organized by redundancy-reduced Groups summary pages that facilitate exploration groups similar proteins. Newly released programmatic are also described, as enhanced training opportunities.

Язык: Английский

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Biophysics-based protein language models for protein engineering

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Март 17, 2024

Protein language models trained on evolutionary data have emerged as powerful tools for predictive problems involving protein sequence, structure, and function. However, these overlook decades of research into biophysical factors governing We propose Mutational Effect Transfer Learning (METL), a model framework that unites advanced machine learning modeling. Using the METL framework, we pretrain transformer-based neural networks simulation to capture fundamental relationships between energetics. finetune experimental sequence-function harness signals apply them when predicting properties like thermostability, catalytic activity, fluorescence. excels in challenging engineering tasks generalizing from small training sets position extrapolation, although existing methods train remain many types assays. demonstrate METL's ability design functional green fluorescent variants only 64 examples, showcasing potential biophysics-based engineering.

Язык: Английский

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The efficient prediction of inflammatory osteolysis caused by polylactic acid through network toxicology and molecular docking strategy

Ecotoxicology and Environmental Safety, Год журнала: 2025, Номер 291, С. 117876 - 117876

Опубликована: Фев. 1, 2025

Polylactic acid (PLA), as a bioplastic, is extensively utilized in bone tissue engineering for its biocompatibility, adaptability and affordability. However, the toxicological research of PLA still limited. The hydrolysis products induced inflammatory response which caused osteolysis mediated by oxidative damage through recruitment macrophages accumulation foreign body multinucleated giant cells, ultimately leading to failure regeneration. lack effective treatments highlights importance finding new therapies. This study systematically investigated potential molecular mechanisms PLA-induced employing network toxicology docking techniques. We first conducted toxicology-based assessment according structure PLA. result from integrating screening targets multiple databases identified 126 associated with osteolysis, then an interaction diagram was constructed. Gene ontology (GO)/KEGG enrichment analysis clarified that may cause via metabolic pathways cancer, well lipid atherosclerosis. Further STRING Cytoscape software screened 25 core including HSP90AA1, AKT1, SRC, STAT1 FYN. found enriched highly correlated covered 18 targets, supporting scientific hypothesis induces osteolysis. Moreover, results confirmed displayed strong binding ability formed stable binding. Taken together, this not only revealed biological mechanism but also provided evidence future prevention treatment inflammation.

Язык: Английский

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Mitochondrial DNA removal is essential for sperm development and activity

The EMBO Journal, Год журнала: 2025, Номер unknown

Опубликована: Фев. 11, 2025

Abstract Active mitochondrial DNA (mtDNA) elimination during spermatogenesis has emerged as a conserved mechanism ensuring the uniparental inheritance in animals. However, given existence of post-fertilization processes degrading sperm mitochondria, physiological significance mtDNA removal is not clear. Here we show that clearance indispensable for development and activity. We uncover previously unappreciated role Poldip2 exonuclease specifically expressed late required Drosophila . Loss impairs elongated spermatids impedes progression individualization complexes strip away cytoplasmic materials organelles. Over time, poldip2 mutant exhibit marked nuclear genome fragmentation, flies become completely sterile. Notably, these phenotypes were rescued by expressing mitochondrially targeted bacterial exonuclease, which ectopically removes mtDNA. Our work illustrates developmental necessity effective cytoplasm at end spermatid morphogenesis, preventing potential nuclear-mitochondrial imbalance mature sperm, activity shut down.

Язык: Английский

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Machine Learning-Based Process Optimization in Biopolymer Manufacturing: A Review

Polymers, Год журнала: 2024, Номер 16(23), С. 3368 - 3368

Опубликована: Ноя. 29, 2024

The integration of machine learning (ML) into material manufacturing has driven advancements in optimizing biopolymer production processes. ML techniques, applied across various stages production, enable the analysis complex data generated throughout identifying patterns and insights not easily observed through traditional methods. As sustainable alternatives to petrochemical-based plastics, biopolymers present unique challenges due their reliance on variable bio-based feedstocks processing conditions. This review systematically summarizes current applications techniques aiming provide a comprehensive reference for future research while highlighting potential enhance efficiency, reduce costs, improve product quality. also shows role algorithms, including supervised, unsupervised, deep

Язык: Английский

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Molecular architecture of synaptic vesicles

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(49)

Опубликована: Ноя. 27, 2024

Synaptic vesicles (SVs) store and transport neurotransmitters to the presynaptic active zone for release by exocytosis. After release, SV proteins excess membrane are recycled via endocytosis, new SVs can be formed in a clathrin-dependent manner. This process maintains complex molecular composition of through multiple recycling rounds. Previous studies explored proteomic analysis fluorescent microscopy, proposing model an average ( 1 ). However, structural heterogeneity architecture individual not well described. Here, we used cryoelectron tomography visualize details isolated from mouse brains inside cultured neurons. We describe several classes small on surface long proteinaceous densities SVs. identified V-ATPases, determined structure using subtomogram averaging, showed them forming with membrane-embedded protein synaptophysin (Syp). Our bioluminescence assay revealed pairwise interactions between vesicle-associated 2 Syp V-ATPase Voe1 domains. Interestingly, V-ATPases were randomly distributed irrespective vesicle size. A subpopulation neurons contained partially assembled clathrin coat icosahedral symmetry. observed under cages clathrin-coated (CCVs). Additionally, preparations within hippocampal baskets without vesicles. their CCVs preferential location proximity cell membrane. advances understanding SVs' diversity architecture.

Язык: Английский

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Raiding nature’s genetic toolbox for UV-C resistance by functional metagenomics

Scientific Reports, Год журнала: 2025, Номер 15(1)

Опубликована: Янв. 2, 2025

Язык: Английский

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Plasticity of BioPhi-Driven Humanness Optimization in ScFv-CD99 Binding Affinity Validated Through AlphaFold, HADDOCK, and MD Simulations

Computational and Structural Biotechnology Journal, Год журнала: 2025, Номер 27, С. 369 - 382

Опубликована: Янв. 1, 2025

BioPhi-guided humanization was utilized to enhance the humanness of a humanized single-chain variable fragment targeting CD99, leading development two variants: HuScFvMT99/3BP and HuScFvMT99/3HY. The variant incorporated framework region modifications, modest improvements in humanness, particularly VH domain, although VL domain remained suboptimal. To address this limitation, HuScFvMT99/3HY designed by combining wild-type with HuScFvMT99/3BP. Molecular dynamics simulations employing AlphaFold2, AlphaFold3, HADDOCK were performed evaluate HuScFv-CD99 peptide complexes. AF2-based demonstrated enhanced binding free energy (ΔGbinding) for both variants compared HuScFvMT99/3WT. However, ΔGbinding values obtained from AF3 HD inconsistent, exhibiting weakest affinity. While patterns derived AlphaFold3 aligned, amino acid decomposition analysis revealed variations interaction coordinates predicted Root-mean-square deviation indicated improved structural stability (0.975 Å) (1.075 relative HuScFvMT99/3WT (1.225 Å). Biolayer interferometry further confirmed that exhibited highest affinity (KD = 1.35 × 10⁻⁷ M) 2.64 3.95 M). Supporting evidence provided ELISA flow cytometry experiments. PITHA high immunogenicity risk all variants, despite displaying larger complementarity-determining (CDR) cavity, more hydrophobic CDR-H3 loop. These findings highlight delicate balance between enhancing preserving functional integrity critical therapeutic antibody development.

Язык: Английский

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Structural, functional, and regulatory evaluation of a cysteine post-translationally modified Gcn5-related N-acetyltransferase

Biochemical and Biophysical Research Communications, Год журнала: 2025, Номер 748, С. 151299 - 151299

Опубликована: Янв. 11, 2025

Polyamines within the cell are tightly regulated by spermidine/spermine N-acetyltransferase (SSAT) enzymes. While several SSATs have been investigated in different bacterial species, there is still a significant gap knowledge about which proteins functional many organisms. For example, while it known that Pseudomonas aeruginosa synthesizes polyamine spermidine, SSAT acetylates this molecule and its importance regulating intracellular polyamines remains unknown. We previously identified candidate Gcn5-related (GNAT) protein from P. (PA2271) could fulfill role since but no further studies were conducted. Here, we explored structure/function relationship of PA2271 determining X-ray crystal structure performing enzyme kinetics assays. also active site residues essential for catalysis substrate binding. As study progressed, encountered results led us to explore four cysteine on activity disulfide bond formation or modification residues. found these important solubility activity, an interrelationship between contribute effects. Furthermore, bonds form C121 C165 speculate may redox regulation activity.

Язык: Английский

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Engineering a thermophilic luciferase variant from Photuris pennsylvanica into a mesophilic-like enzyme for expanded applications potential

International Journal of Biological Macromolecules, Год журнала: 2025, Номер 297, С. 139605 - 139605

Опубликована: Янв. 13, 2025

Язык: Английский

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