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Protein-ligand structure and affinity prediction in CASP16 using a geometric deep learning ensemble and flow matching
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  • Alex Morehead,
  • Jian Liu,
  • Pawan Neupane,
  • Nabin Giri,
  • Jianlin Cheng
Alex Morehead
University of Missouri
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Jian Liu
University of Missouri
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Pawan Neupane
University of Missouri
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Nabin Giri
University of Missouri
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Jianlin Cheng
University of Missouri

Corresponding Author:chengji@missouri.edu

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Abstract

Predicting the structure of ligands bound to proteins is a foundational problem in modern biotechnology and drug discovery, yet little is known about how to combine the predictions of protein-ligand structure (poses) produced by the latest deep learning methods to identify the best poses and how to accurately estimate the binding affinity between a protein target and a list of ligand candidates. Further, a blind benchmarking and assessment of protein-ligand structure and binding affinity prediction is necessary to ensure it generalizes well to new settings. Towards this end, we introduce MULTICOM_ligand, a deep learning-based protein-ligand structure and binding affinity prediction ensemble featuring structural consensus ranking for unsupervised pose ranking and a new deep generative flow matching model for joint structure and binding affinity prediction. Notably, MULTICOM_ligand ranked among the top-5 ligand prediction methods in both protein-ligand structure prediction and binding affinity prediction in the 16th Critical Assessment of Techniques for Structure Prediction (CASP16), demonstrating its efficacy and utility for real-world drug discovery efforts. The source code for MULTICOM_ligand is freely available on GitHub.
26 Jan 2025Submitted to PROTEINS: Structure, Function, and Bioinformatics
29 Jan 2025Submission Checks Completed
29 Jan 2025Assigned to Editor
29 Jan 2025Review(s) Completed, Editorial Evaluation Pending
29 Jan 2025Reviewer(s) Assigned