Enhancing functional proteins through multimodal inverse folding with ABACUS-T

Yufeng Liu, Rui Wu, Xinyu Wang, Sheng Wang, Linghui Chen, Fudong Li, Quan Chen () and Haiyan Liu ()
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Yufeng Liu: University of Science and Technology of China, Department of Rheumatology and Immunology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Hefei National Research Center for Physical Sciences at the Microscale, Center for Advanced Interdisciplinary Science and Biomedicine of IHM
Rui Wu: University of Science and Technology of China, Department of Rheumatology and Immunology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Hefei National Research Center for Physical Sciences at the Microscale, Center for Advanced Interdisciplinary Science and Biomedicine of IHM
Xinyu Wang: University of Science and Technology of China, Department of Rheumatology and Immunology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Hefei National Research Center for Physical Sciences at the Microscale, Center for Advanced Interdisciplinary Science and Biomedicine of IHM
Sheng Wang: Ltd, Oristruct Biotech Co.
Linghui Chen: Ltd, Oristruct Biotech Co.
Fudong Li: University of Science and Technology of China, MOE Key Laboratory for Membraneless Organelles and Cellular Dynamics, School of Life Sciences, Division of Life Sciences and Medicine
Quan Chen: University of Science and Technology of China, Department of Rheumatology and Immunology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Hefei National Research Center for Physical Sciences at the Microscale, Center for Advanced Interdisciplinary Science and Biomedicine of IHM
Haiyan Liu: University of Science and Technology of China, MOE Key Laboratory for Membraneless Organelles and Cellular Dynamics, School of Life Sciences, Division of Life Sciences and Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Structure-based sequence redesign or inverse folding can significantly enhance structural stability but often compromises functional activity when performed using existing models. Here, we introduce ABACUS-T, a multimodal inverse folding model that improves precision and minimizes functional loss. ABACUS-T unifies several important features into one framework: detailed atomic sidechains and ligand interactions, a pre-trained protein language model, multiple backbone conformational states, and evolutionary information from multiple sequence alignment (MSA). Redesigned proteins show notable improvements: an allose binding protein achieves 17-fold higher affinity while retaining conformational change; redesigned endo-1,4-β-xylanase and TEM β-lactamase maintain or surpass wild-type activity; and OXA β-lactamase gains altered substrate selectivity. All achieve substantially increase thermostability (∆Tm ≥ 10 °C). In each test case, these enhancements are achieved by testing only a few sequences, each containing dozens of simultaneously mutated residues. ABACUS-T thus offers a promising tool for reengineering functional proteins in biotechnological applications.

Date: 2025
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DOI: 10.1038/s41467-025-65175-3

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