Locating large, flexible ligands on proteins

J.N. Grad, A. Gigante, C. Wilms, J.N. Dybowski, L. Ohl, C. Ottmann, C. Schmuck, D. Hoffmann

Research output: Contribution to journalArticleAcademicpeer-review

1 Citation (Scopus)

Abstract

Many biologically important ligands of proteins are large, flexible, and in many cases charged molecules that bind to extended regions on the protein surface. It is infeasible or expensive to locate such ligands on proteins with standard methods such as docking or molecular dynamics (MD) simulation. The alternative approach proposed here is scanning of a spatial and angular grid around the protein with smaller fragments of the large ligand. Energy values for complete grids can be computed efficiently with a well-known fast Fourier transform-accelerated algorithm and a physically meaningful interaction model. We show that the approach can readily incorporate flexibility of the protein and ligand. The energy grids (EGs) resulting from the ligand fragment scans can be transformed into probability distributions and then directly compared to probability distributions estimated from MD simulations and experimental structural data. We test the approach on a diverse set of complexes between proteins and large, flexible ligands, including a complex of sonic hedgehog protein and heparin, three heparin sulfate substrates or nonsubstrates of an epimerase, a multibranched supramolecular ligand that stabilizes a protein-peptide complex, a flexible zwitterionic ligand that binds to a surface basin of a Kringle domain, and binding of ATP to a flexible site of an ion channel. In all cases, the EG approach gives results that are in good agreement with experimental data or MD simulations.

Original languageEnglish
Pages (from-to)315-327
Number of pages13
JournalJournal of Chemical Information and Modeling
Volume58
Issue number2
DOIs
Publication statusPublished - 26 Feb 2018

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Ligands
Proteins
energy
simulation
Molecular dynamics
flexibility
Probability distributions
Heparin
Computer simulation
Hedgehog Proteins
interaction
Racemases and Epimerases
Values
Adenosinetriphosphate
Ion Channels
Fast Fourier transforms
Peptides
Sulfates
Membrane Proteins
Adenosine Triphosphate

Cite this

Grad, J. N., Gigante, A., Wilms, C., Dybowski, J. N., Ohl, L., Ottmann, C., ... Hoffmann, D. (2018). Locating large, flexible ligands on proteins. Journal of Chemical Information and Modeling, 58(2), 315-327. https://doi.org/10.1021/acs.jcim.7b00413
Grad, J.N. ; Gigante, A. ; Wilms, C. ; Dybowski, J.N. ; Ohl, L. ; Ottmann, C. ; Schmuck, C. ; Hoffmann, D. / Locating large, flexible ligands on proteins. In: Journal of Chemical Information and Modeling. 2018 ; Vol. 58, No. 2. pp. 315-327.
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Grad, JN, Gigante, A, Wilms, C, Dybowski, JN, Ohl, L, Ottmann, C, Schmuck, C & Hoffmann, D 2018, 'Locating large, flexible ligands on proteins', Journal of Chemical Information and Modeling, vol. 58, no. 2, pp. 315-327. https://doi.org/10.1021/acs.jcim.7b00413

Locating large, flexible ligands on proteins. / Grad, J.N.; Gigante, A.; Wilms, C.; Dybowski, J.N.; Ohl, L.; Ottmann, C.; Schmuck, C.; Hoffmann, D.

In: Journal of Chemical Information and Modeling, Vol. 58, No. 2, 26.02.2018, p. 315-327.

Research output: Contribution to journalArticleAcademicpeer-review

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