Rigidity Strengthening: A Mechanism for Protein–Ligand Binding
Abstract
Protein-ligand binding is essential to almost all life processes. The understanding of protein-ligand interactions is fundamentally important to rational drug and protein design. Based on large scale data sets, we show that protein rigidity strengthening or flexibility reduction is a mechanism in protein-ligand binding. Our approach based solely on rigidity is able to unveil a surprisingly apparently long-range contribution of apparently four residue layers to protein-ligand binding, which has ramifications for drug and protein design. Additionally, the present work reveals that among various pairwise interactions, the short-range ones within the distance of the van der Waals diameter are most important. It is found that the present approach outperforms all other state-of-the-art scoring functions for protein-ligand binding affinity predictions of two benchmark test sets.
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Characterizing non-additive contributions of functional groups helps machine learning-based scoring functions consistently maintain accuracy in binding affinity predictions across a variety of protein-ligand complexes.
“Such a characterization can help machine learning-based SFs consistently maintain their accuracy in binding affinity predictions for a variety of protein–ligand complexes [19–23].”
From Mathematical deep learning for pose and binding affinity prediction and ranking in D3R Grand Challenges (2019) · cites this paper as [20]
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Self-citation
- Authors
- Nguyen, D. D., Xiao, T., Wang, M., & Wei, G.-W.
- Affiliations
- Michigan State University (US)
- Corresponding author
- Wei, Guo-Wei
- Venue
- Journal of Chemical Information and Modeling
- Publisher
- American Chemical Society (ACS)
- Published
- 2017-07-12
- Volume
- 57
- Issue
- 7
- Pages
- 1715-1721
- ISSN
- 1549-9596 (ISSN-L)
- 1549-960X
- OpenAlex
- W2610142609
- Cited by
- 105
- References
- 34
- Citations by year
- 2026: 4 · 2025: 12 · 2024: 11 · 2023: 17 · 2022: 21 · 2021: 17 · 2020: 11 · 2019: 8 · 2018: 4
- FWCI
- 4.72
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Chemical Information and Modeling (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Division of Mathematical Sciences (1721024)
- Division of Information and Intelligent Systems (1302285)
- Center for Mathematical Molecular Biosciences Initiative, Michigan State University
- Topics
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Interaction Studies and Fluorescence Analysis
- Keywords
- protein-ligand binding, protein rigidity, binding affinity prediction, pairwise interactions, van der Waals interactions, long-range interactions, drug design, protein design
- MeSH terms
- Ligands, Protein Binding, Proteins, Computational Biology
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