Data and AI-driven synthetic binding protein discovery

Trends in Pharmacological Sciences, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

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SYNBIP 2.0: epitopes mapping, sequence expansion and scaffolds discovery for synthetic binding protein innovation

Nucleic Acids Research, Journal Year: 2024, Volume and Issue: 53(D1), P. D595 - D603

Published: Oct. 16, 2024

Abstract Synthetic binding proteins (SBPs) represent a pivotal class of artificially engineered proteins, meticulously crafted to exhibit targeted properties and specific functions. Here, the SYNBIP database, comprehensive resource for SBPs, has been significantly updated. These enhancements include (i) featuring 3D structures 899 SBP–target complexes illustrate epitopes (ii) using SBPs in monomer or complex forms with target their sequence space expanded five times 12 025 by integrating structure-based protein generation framework property prediction tool, (iii) offering detailed information on 78 473 newly identified SBP-like scaffolds from RCSB Protein Data Bank, an additional 16 401 555 ones AlphaFold Structure Database, (iv) database is regularly updated, incorporating 153 new SBPs. Furthermore, structural models all have enhanced through application AlphaFold2, clinical statuses concurrently refreshed. Additionally, design methods employed each SBP are now prominently featured database. In sum, 2.0 designed provide researchers essential data, facilitating innovation research, diagnosis therapy. freely accessible at https://idrblab.org/synbip/.

Language: Английский

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Navigating the landscape: A comprehensive overview of computational approaches in therapeutic antibody design and analysis

Advances in protein chemistry and structural biology, Journal Year: 2025, Volume and Issue: unknown, P. 33 - 76

Published: Jan. 1, 2025

Language: Английский

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Atomistic Insights into gp82 Binding: A Microsecond, Million-Atom Exploration of Trypanosoma cruzi Host-Cell Invasion

Biochemistry, Journal Year: 2025, Volume and Issue: unknown

Published: March 28, 2025

Chagas disease, caused by the protozoan Trypanosoma cruzi, affects millions globally, leading to severe cardiac and gastrointestinal complications in its chronic phase. The invasion of host cells T. cruzi is mediated interaction between parasite's glycoprotein gp82 human receptor lysosome-associated membrane protein 2 (LAMP2). While experimental studies have identified a few residues involved this interaction, comprehensive molecular-level understanding has been lacking. In study, we present 1.44-million-atom computational model complex, including over 3300 lipids, glycosylation sites, full molecular representations LAMP2, making it most complete parasite-host date. Using microsecond-long dynamics simulations dynamic network analysis, critical residue interactions, novel regions contact that were previously uncharacterized. Our findings also highlight significance transmembrane domain LAMP2 stabilizing complex. These insights extend beyond traditional hydrogen bond revealing complex cooperative motions facilitate invasion. This study not only confirms key observations but uncovers new targets for therapeutic intervention, offering potential pathway disrupt infection combat disease.

Language: Английский

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Amber Codon Mutational Scanning and Bioorthogonal PEGylation for Epitope Mapping of Antibody Binding Sites on Human Arginase-1

ACS Chemical Biology, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

Epitope mapping is crucial for understanding immunological responses to protein therapeutics. Here, we combined genetic code expansion and bacterial surface display incorporate S-allylcysteine (SAC) into human arginase-1 (hArg1) via Methanococcoides burtonii pyrrolysyl-tRNA synthetase. Using an amber codon deep mutational scanning sequencing workflow, mapped SAC incorporation efficiency across the hArg1 sequence, providing insights structural sequence dependencies of noncanonical amino acid incorporation. We used mutually bioorthogonal allyl/tetrazine azide/DBCO chemistries achieve site-specific PEGylation fluorescent labeling hArg1, revealing side chain reactivity solvent accessibility residues in hArg1. This system was further applied determine binding epitope a monoclonal antibody on high-resolution data impact residue position binding. Our method produces high dimensional efficiency, functionalization enabled by chemistries, therapeutic proteins.

Language: Английский

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AlphaFold3: An Overview of Applications and Performance Insights

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(8), P. 3671 - 3671

Published: April 13, 2025

AlphaFold3, the latest release of AlphaFold developed by Google DeepMind and Isomorphic Labs, was designed to predict protein structures with remarkable accuracy. AlphaFold3 enhances our ability model not only single but also complex biomolecular interactions, including protein–protein protein–ligand docking, protein-nucleic acid complexes. Herein, we provide a detailed examination AlphaFold3’s capabilities, emphasizing its applications across diverse biological fields effectiveness in systems. The strengths new AI are highlighted, dynamic systems, multi-chain assemblies, complicated complexes that were previously challenging depict. We explore role advancing drug discovery, epitope prediction, study disease-related mutations. Despite significant improvements, present review addresses ongoing obstacles, particularly modeling disordered regions, alternative folds, multi-state conformations. limitations future directions discussed as well, an emphasis on potential integration experimental techniques further refine predictions. Lastly, work underscores transformative contribution computational biology, providing insights into molecular interactions revolutionizing accelerated design genomic research.

Language: Английский

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Engineering the Mechanical Stability of a Therapeutic Affibody/PD-L1 Complex by Anchor Point Selection

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 21, 2024

Protein-protein complexes can vary in mechanical stability depending on the direction from which force is applied. Here we investigated anisotropic of a molecular complex between therapeutic non-immunoglobulin scaffold called Affibody and extracellular domain immune checkpoint protein PD-L1. We used combination single-molecule AFM spectroscopy (AFM-SMFS) with bioorthogonal clickable peptide handles, shear stress bead adhesion assays, modeling, steered dynamics (SMD) simulations to understand pulling point dependency mechanostability Affibody:(PD-L1) complex. observed diverse responses anchor point. For example, residue #22 generated an intermediate unfolding event attributed partial PD-L1, while Affibody's N-terminus force-activated catch bond behavior. found that or #47 highest rupture forces, breaking at up ~ 190 pN under loading rates ~10

Language: Английский

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Engineering the Mechanical Stability of a Therapeutic Complex between Affibody and Programmed Death-Ligand 1 by Anchor Point Selection

ACS Nano, Journal Year: 2024, Volume and Issue: 18(46), P. 31912 - 31922

Published: Nov. 8, 2024

Protein-protein complexes can vary in mechanical stability depending on the direction from which force is applied. Here, we investigated of a complex between binding scaffold called Affibody and an immune checkpoint protein Programmed Death-Ligand 1 (PD-L1). We used AFM single-molecule spectroscopy with bioorthogonal clickable peptide handles, shear stress bead adhesion assays, molecular modeling, steered dynamics (SMD) to understand pulling point dependency mechanostability Affibody:(PD-L1) complex. observed wide range rupture forces anchor point. Pulling residue #22 generated intermediate state attributed partially unfolded PD-L1, while Affibody's N-terminus force-activated catch bond. or #47 high forces, breaking at up ∼190 pN under loading rates ∼10

Language: Английский

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