Structural insights into the morpholino nucleic acid/RNA duplex using the new XNA builder Ducque in a molecular modeling pipeline

Author:

Rihon Jérôme1ORCID,Mattelaer Charles-Alexandre12,Montalvão Rinaldo Wander13,Froeyen Mathy1,Pinheiro Vitor Bernardes1,Lescrinier Eveline1ORCID

Affiliation:

1. Laboratory of Medicinal Chemistry, Rega Institute for Medical Research , Herestraat 49, Box 1030, B-3000 Leuven, Belgium

2. Quantum Chemistry and Physical Chemistry , Celestijnenlaan 200f, Box 2404, B-3001, Leuven, Belgium

3. Gain Therapeutics sucursal en España, Barcelona Science Park , Baldiri Reixac 4-10, 08028 Barcelona, Spain

Abstract

Abstract The field of synthetic nucleic acids with novel backbone structures [xenobiotic nucleic acids (XNAs)] has flourished due to the increased importance of XNA antisense oligonucleotides and aptamers in medicine, as well as the development of XNA processing enzymes and new XNA genetic materials. Molecular modeling on XNA structures can accelerate rational design in the field of XNAs as it contributes in understanding and predicting how changes in the sugar–phosphate backbone impact on the complementation properties of the nucleic acids. To support the development of novel XNA polymers, we present a first-in-class open-source program (Ducque) to build duplexes of nucleic acid analogs with customizable chemistry. A detailed procedure is described to extend the Ducque library with new user-defined XNA fragments using quantum mechanics (QM) and to generate QM-based force field parameters for molecular dynamics simulations within standard packages such as AMBER. The tool was used within a molecular modeling workflow to accurately reproduce a selection of experimental structures for nucleic acid duplexes with ribose-based as well as non-ribose-based nucleosides. Additionally, it was challenged to build duplexes of morpholino nucleic acids bound to complementary RNA sequences.

Funder

FWO

KU Leuven Research

Publisher

Oxford University Press (OUP)

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