Flexible backbone assembly and refinement of symmetrical homomeric complexes
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Abstract
Symmetrical homomeric proteins are ubiquitous in every domain of life, and information about their structure is essential to decipher function. The size of these complexes often makes them intractable to high-resolution structure determination experiments. Computational docking algorithms offer a promising alternative for modeling large complexes with arbitrary symmetry. Accuracy of existing algorithms, however, is limited by backbone inaccuracies when using homology-modeled monomers. Here, we present Rosetta SymDock2 with a broad search of symmetrical conformational space using a six-dimensional coarse-grained score function followed by an all-atom flexible-backbone refinement, which we demonstrate to be essential for physically realistic modeling of tightly packed complexes. In global docking of a benchmark set of complexes of different point symmetries-starting from homology-modeled monomers-we successfully dock (defined as predicting three near-native structures in the five top-scoring models) 17 out of 31 cyclic complexes and 3 out of 12 dihedral complexes.
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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 [28]
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- Authors
- Roy Burman, S. S., Yovanno, R. A., & Gray, J. J.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- Gray, Jeffrey J.
- Venue
- Structure
- Publisher
- Elsevier BV
- Published
- 2019-06
- Volume
- 27
- Issue
- 6
- Pages
- 1041-1051.e8
- ISSN
- 0969-2126 (ISSN-L)
- PMC
- PMC6719319
- OpenAlex
- W2951033067
- Cited by
- 18
- References
- 55
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 3 · 2023: 2 · 2022: 1 · 2021: 3 · 2020: 3 · 2019: 2
- FWCI
- 0.74
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Structure (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (R01-GM078221, T32-GM008403)
- National Science Foundation (1507736)
- Maryland Advanced Research Computing Center
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Keywords
- homology modeling, cyclic complexes, point symmetry, conformational search
- MeSH terms
- Algorithms, Protein Binding, Protein Conformation, Proteins, Reproducibility of Results, Computational Biology, Protein Interaction Mapping, Protein Multimerization, Molecular Docking Simulation
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