Modeling protein quaternary structure of homo- and hetero-oligomers beyond binary interactions by homology

By Martino Bertoni, Florian Kiefer, Marco Biasini, Lorenza Bordoli, Torsten Schwede. 2017

773 citations recorded by the source corpus.

Cellular processes often depend on interactions between proteins and the formation of macromolecular complexes. The impairment of such interactions can lead to deregulation of pathways resulting in disease states, and it is hence crucial to gain insights into the nature of macromolecular assemblies. Detailed structural knowledge about complexes and protein-protein interactions is growing, but experimentally determined three-dimensional multimeric assemblies are outnumbered by complexes supported by non-structural experimental evidence. Here, we aim to fill this gap by modeling multimeric structures by homology, only using amino acid sequences to infer the stoichiometry and the overall structure of the assembly. We ask which properties of proteins within a family can assist in the prediction of correct quaternary structure. Specifically, we introduce a description of protein-protein interface conservation as a function of evolutionary distance to reduce the noise in deep multiple sequence alignments. We also define a distance measure to structurally compare homologous multimeric protein complexes. This allows us to hierarchically cluster protein structures and quantify the diversity of alternative biological assemblies known today. We find that a combination of conservation scores, structural clustering, and classical interface descriptors, can improve the selection of homologous protein templates leading to reliable models of protein complexes.

Subfields: Molecular Biology, Computational Biology & Bioinformatics

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Citations in the corpus

SWISS-MODEL: homology modelling of protein structures and complexes (2018, positive): “Notably, the interface quality of the model, i.e. QS-score = 0.52, agrees very well with its estimated accuracy, i.e. QSQE = 0.54.”
Assessment of protein assembly prediction in CASP13 (2019, methodology): “We used the QS-score algorithm [24] (all targets exceptH1021) andQSalign [25] (H1021) for this purpose.”
Protein complex prediction with AlphaFold-Multimer (2021, background): “We found empirically that a 50:50 ratio of interface cropping to contiguous cropping worked best for multimers (always contiguous cropping for monomers).”
CAMEO - Perspectives on the future of fully automated evaluation of structure prediction methods (2021, neutral): “The complex models are evaluated with the oligo-lDDT score, 15 which is a modified version of lDDT that looks at the whole complex and accounts for missing or extra chains; the MM-align-based 12 TM-score and RMSD, which are superposition-dependent; and the QS-score, 11 which looks specifically at th”
Flexible backbone assembly and refinement of symmetrical homomeric complexes (2018, background): “Instead, incorporating symmetry information while homology modeling provides a promising avenue, which servers like Robetta (Park et al., 2018), SWISS-MODEL Oligo (Bertoni et al., 2017) and GalaxyHomomer (Baek et al., 2017) have recently demonstrated.”
InterEvDock2: an expanded server for protein docking using evolutionary and biological information from homology models and multimeric inputs (2018, methodology): “Recently released servers taking protein sequences as input for homology-based interface modeling include SnapDock (6), HOMCOS (7) and SWISS-MODEL Oligo (8).”
New prediction categories in CASP15 (2023, background): “This is the oligomeric Template Modeling score (TM-score) 49 for overall topology (SCORE) and the contact based QS-score 50 which is interface centric (QSCORE).”
Improved multimer prediction using massive sampling with AlphaFold in CASP15 (2023, methodology): “The101 chain mapping routine in QS-score (Bertoni et al., 2017) was used to determine the optimal chain102 mapping.”
Assessment of protein assembly prediction in CASP12 (2018, methodology): “19 The sequence templates and QS-scores for each target assembly suitable for homology modeling are provided in Supporting information Table S1.”