# Probing the Structural Dynamics of the Unbound MAX Protein: Insights from Well-Tempered Metadynamics

## TL;DR

This study reveals a stable structure of the MAX protein, which could help in developing drugs to target cancer-related MYC/MAX interactions.

## Contribution

The study identifies a stable conformation of unbound MAX protein using metadynamics, revealing potential druggable sites.

## Key findings

- MAX protein can adopt a stable, thermodynamically favorable conformation.
- Metastable structural motifs in MAX may serve as potential drug targets.
- The findings provide a structural framework for future drug design targeting the MYC/MAX axis.

## Abstract

One of most relevant
challenges in tumorigenesis is the
association
of MYC and MAX proteins, whose related cancers remain undrugged. In
particular, the disordered regions shown by those oncogenes make their
structural characterization and the development of new drugs a truly
hard task. To address these challenges, we employed the enhanced-sampling
well-tempered metadynamics method to systematically explore the conformational
space of the unbound MAX protein. Our results revealed, for the first
time, a well-defined and thermodynamically favorable conformation
of monomeric MAX. This is a remarkable finding, as it demonstrates
that regions of MAX previously considered persistently disordered
are capable of adopting stable, folded structures under specific conditions.
Moreover, our findings also suggest that the metastable structural
motifs observed in this work may harbor druggable sites, particularly
relevant for strategies aiming to target MAX directly or to disrupt
its interaction with MYC, thereby modulating oncogenic signaling pathways.
The present study establishes a new structural framework for understanding
the dynamics of MAX and provides a foundation for future structure-based
drug design targeting the MYC/MAX axis. Finally, our work offers a
strategic blueprint for investigating similarly challenging drug targets.