Predicting aptamer sequences that interact with target proteins using an aptamer-protein interaction classifier and a Monte Carlo tree search approach

Abstract

Oligonucleotide-based aptamers, which have a three-dimensional structure with a single-stranded fragment, feature various characteristics with respect to size, toxicity, and permeability. Accordingly, aptamers are advantageous in terms of diagnosis and treatment and are materials that can be produced through relatively simple experiments. Systematic evolution of ligands by exponential enrichment (SELEX) is one of the most widely used experimental methods for generating aptamers; however, it is highly expensive and time-consuming. To reduce the related costs, recent studies have used in silico approaches, such as aptamer-protein interaction (API) classifiers that use sequence patterns to determine the binding affinity between RNA aptamers and proteins. Some of these methods generate candidate RNA aptamer sequences that bind to a target protein, but they are limited to producing candidates of a specific size. In this study, we present a machine learning approach for selecting candidate sequences of various sizes that have a high binding affinity for a specific sequence of a target protein. We applied the Monte Carlo tree search (MCTS) algorithm for generating the candidate sequences using a score function based on an API classifier. The tree structure that we designed with MCTS enables nucleotide sequence sampling, and the obtained sequences are potential aptamer candidates. We performed a quality assessment using the scores of docking simulations. Our validation datasets revealed that our model showed similar or better docking scores in ZDOCK docking simulations than the known aptamers. We expect that our method, which is size-independent and easy to use, can provide insights into searching for an appropriate aptamer sequence for a target protein during the simulation step of SELEX.

Myogenetic Oligodeoxynucleotides as Anti-Nucleolin Aptamers Inhibit the Growth of Embryonal Rhabdomyosarcoma Cells

“…Nuclear nucleolin was defined as their target a posteriori. Both 18-base iSN04 and 26-base AS1411 have been confirmed to be incorporated into the cytoplasm without any carriers or transfection reagents [ 16 , 24 ], probably because of their short sequences compared to the average length of the known aptamers (51 bases) [ 46 ]. Single-strand short DNA is usually taken up by cells through the endocytic process termed gymnosis [ 47 ], which enables compact DNA aptamers to target cytoplasmic and nuclear proteins.…”

Novel Design of RNA Aptamers as Cancer Inhibitors and Diagnosis Targeting the Tyrosine Kinase Domain of the NT-3 Growth Factor Receptor Using a Computational Sequence-Based Approach

“…The aptamer selection with SELEX has multiple drawbacks that restrict its effectiveness and make it challenging to produce high-affinity aptamers. The SELEX method requires numerous rounds of selection and enrichment, which makes the process last for months [ 30 ]. Computational approaches are promising tools to overcome the time and costs of in vitro aptamer selection.…”

Myogenetic oligodeoxynucleotides as anti-nucleolin aptamers inhibit the growth of embryonal rhabdomyosarcoma cells

“…Nuclear nucleolin was defined as the target a posteriori. Both 18-base iSN04 and 26-base AS1411 have been confirmed to be incorporated into the cytoplasm without any carriers or transfection reagents [11,18], probably because of their short sequences compared to the average length of the known aptamers (51 bases) [31]. Single-strand short DNA is usually taken up by cells through the endocytic process termed gymnosis [32], which enables compact DNA aptamers to target cytoplasmic and nuclear proteins.…”