We have improved the original Rosetta centroid/backbone decoy set by increasing the number of proteins and frequency of near native models and by building on sidechains and minimizing clashes. The new set consists of 1,400 model structures for 78 different and diverse protein targets and provides a challenging set for the testing and evaluation of scoring functions. We evaluated the extent to which a variety of all-atom energy functions could identify the native and close-to-native structures in the new decoy sets. Of various implicit solvent models, we found that a solvent-accessible surface area-based solvation provided the best enrichment and discrimination of close-to-native decoys. The combination of this solvation treatment with Lennard Jones terms and the original Rosetta energy provided better enrichment and discrimination than any of the individual terms. The results also highlight the differences in accuracy of NMR and X-ray crystal structures: a large energy gap was observed between native and non-native conformations for X-ray structures but not for NMR structures.
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http://dx.doi.org/10.1002/prot.10454 | DOI Listing |
J Chem Inf Model
December 2024
Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, Nanjing 211198, China.
Developing selective kinase inhibitors remains a formidable challenge in drug discovery because of the highly conserved structural information on adenosine triphosphate (ATP) binding sites across the kinase family. Tailoring docking protocols to identify promising kinase inhibitor candidates for optimization has long been a substantial obstacle to drug discovery. Therefore, we introduced "Kinase-Bench," a pioneering benchmark suite designed for an advanced virtual screen, to improve the selectivity and efficacy of kinase inhibitors.
View Article and Find Full Text PDFJ Cheminform
November 2024
Arontier Co., 241, Gangnam-daero, Seocho-gu, Seoul, 06735, Republic of Korea.
We introduce an advanced model for predicting protein-ligand interactions. Our approach combines the strengths of graph neural networks with physics-based scoring methods. Existing structure-based machine-learning models for protein-ligand binding prediction often fall short in practical virtual screening scenarios, hindered by the intricacies of binding poses, the chemical diversity of drug-like molecules, and the scarcity of crystallographic data for protein-ligand complexes.
View Article and Find Full Text PDFbioRxiv
September 2024
Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
Diffusion models have shown promise in addressing the protein docking problem. Traditionally, these models are used solely for sampling docked poses, with a separate confidence model for ranking. We introduce DFMDock (Denoising Force Matching Dock), a diffusion model that unifies sampling and ranking within a single framework.
View Article and Find Full Text PDFVet Microbiol
November 2024
Veterinary Diagnostic Laboratory, Veterinary Diagnostic and Production Animal Medicine, Iowa State University, Ames, IA, USA. Electronic address:
Mol Cell Proteomics
November 2024
Bioinformatics Solutions Inc, Waterloo, Ontario, Canada. Electronic address:
De novo peptide sequencing is one of the most fundamental research areas in mass spectrometry-based proteomics. Many methods have often been evaluated using a couple of simple metrics that do not fully reflect their overall performance. Moreover, there has not been an established method to estimate the false discovery rate (FDR) of de novo peptide-spectrum matches.
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