Rational design of an XNA ligase through docking of unbound nucleic acids to toroidal proteins

Xenobiotic nucleic acids (XNA) are nucleic acid analogues not present in nature that can be used for the storage of genetic information. In vivo XNA applications could be developed into novel biocontainment strategies, but are currently limited by the challenge of developing XNA processing enzymes s...

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Bibliographic Details
Published in:Nucleic acids research 2019-07, Vol.47 (13), p.7130-7142
Main Authors: Vanmeert, Michiel, Razzokov, Jamoliddin, Mirza, Muhammad Usman, Weeks, Stephen D, Schepers, Guy, Bogaerts, Annemie, Rozenski, Jef, Froeyen, Mathy, Herdewijn, Piet, Pinheiro, Vitor B, Lescrinier, Eveline
Format: Article
Language:English
Subjects:
Computer Simulation
Deoxyribonuclease BamHI - metabolism
DNA Ligases - chemistry
DNA Ligases - metabolism
DNA Viruses - enzymology
DNA, Viral - metabolism
Models, Chemical
Molecular Docking Simulation
Mutagenesis, Site-Directed
Nucleic Acid Conformation
Protein Binding
Protein Conformation
Structure-Activity Relationship
Substrate Specificity
Synthetic Biology and Bioengineering
Templates, Genetic
Viral Proteins - chemistry
Viral Proteins - metabolism
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Summary:Xenobiotic nucleic acids (XNA) are nucleic acid analogues not present in nature that can be used for the storage of genetic information. In vivo XNA applications could be developed into novel biocontainment strategies, but are currently limited by the challenge of developing XNA processing enzymes such as polymerases, ligases and nucleases. Here, we present a structure-guided modelling-based strategy for the rational design of those enzymes essential for the development of XNA molecular biology. Docking of protein domains to unbound double-stranded nucleic acids is used to generate a first approximation of the extensive interaction of nucleic acid processing enzymes with their substrate. Molecular dynamics is used to optimise that prediction allowing, for the first time, the accurate prediction of how proteins that form toroidal complexes with nucleic acids interact with their substrate. Using the Chlorella virus DNA ligase as a proof of principle, we recapitulate the ligase's substrate specificity and successfully predict how to convert it into an XNA-templated XNA ligase.
ISSN:0305-1048
1362-4962
DOI:10.1093/nar/gkz551