# In Silico Characterization of ADAR1: Structure, Dynamics, and Functional Implications

## TL;DR

This study uses computational methods to model the structure and dynamics of the ADAR1 protein, revealing how its flexible regions contribute to RNA editing and potential therapeutic applications.

## Contribution

The study provides novel computational models and dynamic insights into the full-length ADAR1 protein, linking structural stability with functional flexibility.

## Key findings

- The dsRBD3 and CDD domains of ADAR1 are structurally stable, important for binding and catalytic activity.
- ZBDs and dsRBD1/2 domains show extensive flexibility, aiding RNA recognition through conformational changes.
- Free-energy landscape analysis reveals multiple low-energy conformations, emphasizing dynamic regulation of ADAR1 function.

## Abstract

Adenosine deaminase acting on RNA 1 (ADAR1) is an essential RNA-editing enzyme responsible for the hydrolytic deamination of adenosine to inosine (A-to-I) in double-stranded RNA. This editing mechanism plays a critical role in gene regulation, particularly in neural and immune contexts. Dysregulation of ADAR1 activity has been implicated in neurological disorders, cancer progression, and immune dysfunction, making ADAR1 an emerging therapeutic target. However, progress in therapeutic development has been hindered by the lack of structural insight into the full-length protein and how its dynamic behavior influences RNA-editing specificity and protein–protein interactions. In this study, we present computational models of the full-length ADAR1p150 isoform generated by homology modeling and further analyzed using molecular dynamics (MD) simulations and principal component analysis (PCA). Our analyses reveal that the dsRBD3 and CDD remain structurally stable, crucial for protein binding and catalytic function, whereas ZBDs and dsRBD1/2 exhibit extensive flexibility, particularly in inter-domain loops, facilitating RNA recognition indicative of conformational selection and fly-casting mechanisms. Free-energy landscape mapping identifies multiple low-energy conformations, highlighting conserved domain cores and flexible loop arrangements. Together, these findings underscore the importance of ADAR1’s dynamic architecture in regulating its function. By linking static structural information with dynamic behavior, the full-length models and dynamic insights presented here provide a valuable framework for future studies of ADAR1 complex formation, editing specificity, and therapeutic targeting.