Refinement of protein-protein complexes in contact map space with metadynamics simulations
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Abstract Accurate protein‐protein complex prediction, to atomic detail, is a challenging problem. For flexible docking cases, current state‐of‐the‐art docking methods are limited in their ability to exhaustively search the high dimensionality of the problem space. In this study, to obtain more accurate models, an investigation into the local optimization of initial docked solutions is presented with respect to a reference crystal structure. We show how physics‐based refinement of protein‐protein complexes in contact map space (CMS), within a metadynamics protocol, can be performed. The method uses 5 times replicated 10 ns simulations for sampling and ranks the generated conformational snapshots with ZRANK to identify an ensemble of n snapshots for final model building. Furthermore, we investigated whether the reconstructed free energy surface (FES), or a combination of both FES and ZRANK, referred to as CSα, can help to reduce snapshot ranking error.
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Despite significant progress, the local refinement problem remains a challenge, especially in cases of conformational changes in the backbone.
“However, despite significant progress in this direction [26–29], the problem remains a challenge, especially in cases of conformational changes in the backbone.”
From Challenges in protein docking (2020) · cites this paper as [29]
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- Authors
- Pfeiffenberger, E., & Bates, P. A.
- Affiliations
- The Francis Crick Institute (GB)
- Corresponding author
- Bates, Paul A.
- Venue
- Proteins Structure Function and Bioinformatics
- Publisher
- Wiley
- Published
- 2018-10-30
- Volume
- 87
- Issue
- 1
- Pages
- 12-22
- ISSN
- 0887-3585 (ISSN-L)
- 1097-0134
- PMC
- PMC6492248
- OpenAlex
- W2899279414
- Cited by
- 15
- References
- 50
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 1 · 2023: 2 · 2022: 2 · 2021: 2 · 2020: 3 · 2019: 1 · 2018: 1
- FWCI
- 0.62
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Proteins Structure Function and Bioinformatics (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Figshare (submittedVersion, cc-by)
- The Francis Crick Institute (cc-by)
- Funders
- Cancer Research UK (FC001003)
- Medical Research Council (FC001003)
- Wellcome Trust (FC001003)
- Francis Crick Institute (FC001003)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- metadynamics, flexible docking, local optimization, conformational ensembles, free energy landscape
- MeSH terms
- Computer Simulation, Humans, Models, Molecular, Nerve Tissue Proteins, Protein Binding, Protein Conformation, Kinesins, Multiprotein Complexes, Adaptor Proteins, Signal Transducing, Protein Interaction Domains and Motifs, Molecular Docking Simulation
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