# Predicted IL-18/IL-18R Binding Improvement Through Protein Interface Modification with Computer-Aided Design

## TL;DR

This study uses computer modeling to design mutations in IL-18 that improve its binding to receptors, potentially enhancing its cancer-fighting potential.

## Contribution

A novel computer-aided design strategy for improving IL-18 activity through protein interface modification.

## Key findings

- Four candidate mutations were predicted to enhance IL-18 receptor binding and stability.
- MD simulations showed no loss of conformational stability but increased flexibility in the β8–β9 hairpin loop.
- The mutations may improve IL-18 biological activity, though full complex simulations are still needed.

## Abstract

Cytokine-mediated immunotherapy has rapidly emerged as an effective alternative approach for cancer treatment by modulating the anti-tumor response. Interleukin-18 (IL-18) is considered as a promising cancer therapeutic agent due to the ability of cytokines to inhibit cancer by enhancing natural killer (NK) cell and cytotoxic T cell responses. Since the activity of IL-18 is required for the specific binding to IL-18 receptors, the modification of binding residue at the protein interface is an attractive strategy for IL-18 activity enhancement. The aim of this study was to design and predict mutations increasing the activity of IL-18 through computational structure-based energy calculation and molecular dynamic simulations. Four candidate mutations, E6M, E6M+N111S+R131G, E6M+K129M+R131G, and E6M+N111S+K129M+R131G, could affect/facilitate the receptor binding and stability compared to the wild-type via electrostatic interaction. MD simulations demonstrated that the predicted mutation on IL-18 had no influence on the overall conformation stability, but increased flexibility in the β8–β9 hairpin loop. Furthermore, the dynamic behavior suggested that these candidates could be an alternative for the improvement of IL-18 biological activity, though the full simulation of the IL-18 complex remains necessary. In summary, this study offered a computer-aided design strategy which was of beneficial use in the design and development of IL-18 to increase its cytokine potency and efficiency.