Accelerated Structural Prediction of Flexible Protein–Ligand Complexes: The SLICE Method
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Abstract
The work in this submission presents a molecular simulation technique that is able to overcome induced-fit binding issues with a uniquely challenging binding site. This method differs from commercially available methods in that we use a combined software approach that allows users to patch together inexpensive and academically available programs. Our method also differs fundamentally in how the potential energy of the interaction is explored and lends itself to the success in modeling our test system. As an added benefit, our test system is CBX8, an epigenetic reader protein and speculative target for chemotherapy. The method was not only successful in matching crystal structure data, but uncovered a number of induced-fit structural features of the binding motif that are useful in the design of potential inhibitors for this protein.
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Cites
Markov state models of biomolecular conformational dynamics
Chodera, J. D., & Noé, F. (2014) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2014.04.002 · Cited by 776 · see citing works
Modeling protein–protein and protein–peptide complexes: CAPRI 6th edition
Lensink, M. F., Velankar, S., & Wodak, S. J. (2017) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.25215 · Cited by 222 · see citing works
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- Authors
- McFarlane, J. M. B., Krause, K. D., & Paci, I.
- Affiliations
- University of Victoria (CA)
- Corresponding author
- McFarlane, James M. B.
- Paci, Irina
- Venue
- Journal of Chemical Information and Modeling
- Publisher
- American Chemical Society (ACS)
- Published
- 2019-11-06
- Volume
- 59
- Issue
- 12
- Pages
- 5263-5275
- ISSN
- 1549-9596 (ISSN-L)
- 1549-960X
- OpenAlex
- W2983987605
- Cited by
- 4
- References
- 2
- Citations by year
- 2021: 1 · 2020: 2 · 2019: 1
- FWCI
- 0.85
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Journal of Chemical Information and Modeling (publishedVersion)
- ChemRxiv (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Figshare (submittedVersion, cc-by-nc-nd)
- Funders
- University of Victoria
- Natural Sciences and Engineering Research Council of Canada (RGPIN-2016-04529)
- 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 › Receptor Mechanisms and Signaling
- Keywords
- slice method, induced fit, protein-ligand binding, accelerated molecular dynamics, AutoDock Vina, CBX8, H3K9me3, protein conformational ensembles
- MeSH terms
- Ligands, Protein Conformation, Time Factors, Molecular Dynamics Simulation, Polycomb Repressive Complex 1
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