IPRO+/−: Computational Protein Design Tool Allowing for Insertions and Deletions

Insertions and deletions (indels) in protein sequences alter the residue spacing along the polypeptide backbone and consequently open up possibilities for tuning protein function in a way that is inaccessible by amino acid substitution alone. We describe an optimization-based computational protein r...

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Bibliographic Details
Published in:Structure (London) 2020-12, Vol.28 (12), p.1344-1357.e4
Main Authors: Chowdhury, Ratul, Grisewood, Matthew J., Boorla, Veda Sheersh, Yan, Qiang, Pfleger, Brian F., Maranas, Costas D.
Format: Article
Language:English
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Summary:Insertions and deletions (indels) in protein sequences alter the residue spacing along the polypeptide backbone and consequently open up possibilities for tuning protein function in a way that is inaccessible by amino acid substitution alone. We describe an optimization-based computational protein redesign approach centered around predicting beneficial combinations of indels along with substitutions and also obtain putative substrate-docked structures for these protein variants. This modified algorithmic capability would be of interest for enzyme engineering and broadly inform other protein design tasks. We highlight this capability by (1) identifying active variants of a bacterial thioesterase enzyme (‘TesA) with experimental corroboration, (2) recapitulating existing active TEM-1 β-Lactamase sequences of different sizes, and (3) identifying shorter 4-Coumarate:CoA ligases with enhanced in vitro activities toward non-native substrates. A separate PyRosetta-based open-source tool, Indel-Maker (http://www.maranasgroup.com/software.htm), has also been created to construct computational models of user-defined protein variants with specific indels and substitutions. [Display omitted] •Novel protein design tool to predict amino acid indels (and substitutions)•Family sequence alignment gives indel probability at a given residue position•Sampling full sequence space accessible to protein's family by varying chain length•Guarantees faster recovery of indels than random sequence design (p < 10−15) Chowdhury et al. describe an optimization-based protein design tool to identify combinations of protein residue positions, which can allow extra amino acids to be inserted, altered, or even removed from the sequence to arrive at a sequence whose corresponding structure achieves a desired binding affinity with a target molecule.
ISSN:0969-2126
1878-4186
DOI:10.1016/j.str.2020.08.003