Mol Ther
Division of Biology and Biological Engineering, California Institute of Technology, 1200 E California, Boulevard, Pasadena, CA 91125, USA. Electronic address:
Published: June 2024
Deep-learning-based methods for protein structure prediction have achieved unprecedented accuracy, yet their utility in the engineering of protein-based binders remains constrained due to a gap between the ability to predict the structures of candidate proteins and the ability toprioritize proteins by their potential to bind to a target. To bridge this gap, we introduce Automated Pairwise Peptide-Receptor Analysis for Screening Engineered proteins (APPRAISE), a method for predicting the target-binding propensity of engineered proteins. After generating structural models of engineered proteins competing for binding to a target using an established structure prediction tool such as AlphaFold-Multimer or ESMFold, APPRAISE performs a rapid (under 1 CPU second per model) scoring analysis that takes into account biophysical and geometrical constraints. As proof-of-concept cases, we demonstrate that APPRAISE can accurately classify receptor-dependent vs. receptor-independent adeno-associated viral vectors and diverse classes of engineered proteins such as miniproteins targeting the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike, nanobodies targeting a G-protein-coupled receptor, and peptides that specifically bind to transferrin receptor or programmed death-ligand 1 (PD-L1). APPRAISE is accessible through a web-based notebook interface using Google Colaboratory (https://tiny.cc/APPRAISE). With its accuracy, interpretability, and generalizability, APPRAISE promises to expand the utility of protein structure prediction and accelerate protein engineering for biomedical applications.
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http://dx.doi.org/10.1016/j.ymthe.2024.04.003 | DOI Listing |
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College of Agriculture & Biotechnology, Zhejiang University, Hangzhou, 310058, China; Zhejiang Key Laboratory of Horticultural Crop Quality Improvement, Zhejiang University, Hangzhou, 310058, China. Electronic address:
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College of Food Science and Engineering, Bohai University, Jinzhou, Liaoning, China.
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Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, New York 14853, United States.
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Ottawa Hospital Research Institute & CHEO Research Institute, Pediatrics, Ottawa, Ontario, Canada.
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View Article and Find Full Text PDFAnal Chem
January 2025
Department of Chemistry, University of California, Davis, California 95616, United States.
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