Modelling aptamers with nucleic acid mimics (NAM): From sequence to three-dimensional docking

PLoS One. 2022 Mar 23;17(3):e0264701. doi: 10.1371/journal.pone.0264701. eCollection 2022.

Abstract

Aptamers are single-stranded oligonucleotides, formerly evolved by Systematic Evolution of Ligands by EXponential enrichment (SELEX), that fold into functional three-dimensional structures. Such conformation is crucial for aptamers' ability to bind to a target with high affinity and specificity. Unnatural nucleotides have been used to develop nucleic acid mimic (NAM) aptamers with increased performance, such as biological stability. Prior knowledge of aptamer-target interactions is critical for applying post-SELEX modifications with unnatural nucleotides since it can affect aptamers' structure and performance. Here, we describe an easy-to-apply in silico workflow using free available software / web servers to predict the tertiary conformation of NAM, DNA and RNA aptamers, as well as the docking with the target molecule. Representative 2'-O-methyl (2'OMe), locked nucleic acid (LNA), DNA and RNA aptamers, with experimental data deposited in Protein Data Bank, were selected to validate the workflow. All aptamers' tertiary structure and docking models were successfully predicted with good structural similarity to the experimental data. Thus, this workflow will boost the development of aptamers, particularly NAM aptamers, by assisting in the rational modification of specific nucleotides and avoiding trial-and-error approaches.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aptamers, Nucleotide* / chemistry
  • Ligands
  • Nucleic Acid Conformation
  • Nucleic Acids*
  • SELEX Aptamer Technique / methods
  • Software

Substances

  • Aptamers, Nucleotide
  • Ligands
  • Nucleic Acids

Grants and funding

This work was financially supported by: Project POCI-01-0145-FEDER-028659, funded by FEDER funds through COMPETE2020 – Programa Operacional Competitividade e Internacionalização (POCI) and by national funds (PIDDAC) through FCT/MCTES; Base Funding - UIDB/00511/2020 of the Laboratory for Process Engineering, Environment, Biotechnology and Energy – LEPABE - funded by national funds through the FCT/MCTES (PIDDAC). RO thanks FCT for the PhD Fellowship SFRH/BD/138883/2018. OD acknowledges FCT for the Assistant Research contract obtained under CEEC Individual 2018.