Computational Design of Self-Assembling Cyclic Protein Homo-oligomers

By J. Fallas, G. Ueda, W. Sheffler, Vanessa Nguyen, D. McNamara, B. Sankaran, J. H. Pereira, F. Parmeggiani, T. Brunette, D. Cascio and 3 more. 2016

137 citations recorded by the source corpus.

Self-assembling cyclic protein homo-oligomers play important roles in biology and the ability to generate custom homo-oligomeric structures could enable new approaches to probe biological function. Here we report a general approach to design cyclic homo-oligomers that employs a new residue pair transform method for assessing the design ability of a protein-protein interface. This method is sufficiently rapid to enable systematic enumeration of cyclically docked arrangements of a monomer followed by sequence design of the newly formed interfaces. We use this method to design interfaces onto idealized repeat proteins that direct their assembly into complexes that possess cyclic symmetry. Of 96 designs that were experimentally characterized, 21 were found to form stable monodisperse homo-oligomers in solution, and 15 (4 homodimers, 6 homotrimers, 6 homotetramers and 1 homopentamer) had solution small angle X-ray scattering data consistent with the design models. X-ray crystal structures were obtained for five of the designs and each of these were shown to be very close to their design model.

Subfields: Molecular Biology

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Citations in the corpus

Perturbing the energy landscape for improved packing during computational protein design (2020, unknown): “To do so, we used a database of residue-pair interactions observed in structures from the PDB, as created in Fallas, et al. 27 We considered all interactions involving either alanine, phenylalanine, isoleucine, leucine, or valine at one site in the pair, and either phenylalanine, isoleucine, leucine”
Essentials of de novo protein design: Methods and applications (2018, methodology): “De novo repeat proteins tend to have large surfaces that allow a large number of amino acid modifications, and have enabled the engineering of de novo macromolecular assemblies with large protein–protein interfaces.(31) De novo protein design though parametric approaches has proven to be an excellen”
Generation of ordered protein assemblies using rigid three-body fusion (2020, unknown): “Interface design is compatible with the free rotation and translation of building blocks along their axes (14), so the set of valid geometric solutions is technically unlimited.”
Recent advances in de novo protein design: Principles, methods, and applications (2021, methodology): “Homo-oligomers with cyclic symmetries were designed by systematic enumeration of arrangements of the monomers followed by the interface design (139).”
Efficient Flexible Backbone Protein-Protein Docking for Challenging Targets (2017, methodology): “With this idea in mind, we developed Motif Dock Score (MDS) based on the residue-pair transform (RPX) framework (32) for interface design.”
Design of multi-scale protein complexes by hierarchical building block fusion (2021, background): “Six (6) N-terminal and 24 C-terminal fusions were selected and experimentally tested.”
Flexible backbone assembly and refinement of symmetrical homomeric complexes (2018, methodology): “MDS is based on a residue-pair transform framework (Fallas et al., 2017).”
Hallucinating protein assemblies (2022, background): “While there have been a number of successes ( 8 – 10 ), current approaches require specification of the structure of the protomers in advance, and with the exception of parametrically designed helical bundles ( 11 , 12 ), have involved rigid body docking of previously characterized monomers into…”
Modular repeat protein sculpting using rigid helical junctions (2020, unknown): “Incorporation of RPX motifs during low-resolution backbone sampling increases the downstream yield of well-packed designs 100-fold ( SI Appendix , Fig.”