# In silico characterization of the interaction of AKR1B1 with the deacetylase activation domain (DAD)

## TL;DR

This study uses computational methods to better understand how AKR1B1 interacts with the DAD domain in cancer progression.

## Contribution

A new stable model of the DAD/AKR1B1 complex and six key interaction residues are identified through in silico analysis.

## Key findings

- A new AKR1B1 model shows increased structural stability and lower ΔG compared to previous models.
- Six hotspot residues in AKR1B1, including L289, were identified as critical for the DAD interaction.
- The findings suggest new hypotheses for the DAD/AKR1B1 interaction and future experimental validation.

## Abstract

The aldo-keto reductase family 1 member B1 (AKR1B1) plays a key role in cancer progression by competing with histone deacetylase 3 to bind to the deacetylase activation domain (DAD) of the nuclear receptor corepressor SMRT. Previous studies showed that the L289A mutation in AKR1B1 disrupts its ability to form a dimer with DAD but further details of this interaction remain uncharacterized. This study aimed to model the DAD/AKR1B1 dimer by molecular docking and characterize the complex using molecular dynamics simulations. We identified a new model with increased structural stability for AKR1B1, reduced disruption of secondary structures of DAD, and lower ΔG than a previously reported one. In silico mutagenesis of AKR1B1 assessed the contributions from individual residues. We identified six hotspot residues that mediate the complex interface. Those residues are located in the α8 and H2 alpha helices of AKR1B1 and include the experimentally determined L289. These results propose new hypotheses regarding the interaction between DAD and AKR1B1, guiding future experimental approaches.