# Metal‐Coordination Specificity and Structural Dynamics of C. elegans Metallothionein I: Insights From 3D Modeling and MD Simulations

## TL;DR

This study explores how a protein from C. elegans interacts with different metal ions, revealing how metal binding affects its structure and stability.

## Contribution

The study provides new insights into the structural dynamics and metal coordination specificity of C. elegans metallothionein I using 3D modeling and MD simulations.

## Key findings

- The metal-free form of MTL-1 is highly flexible and disordered, with most of its structure composed of coils, bends, and turns.
- Metal binding, especially with Zn2+, Cd2+, Cu2+, and Hg2+, increases structural stability and reduces flexibility.
- Pb2+ binding results in a less stable and more dynamic structure compared to other metal ions.

## Abstract

Metallothioneins (MTLs) are small, cysteine‐rich proteins known for their ability to bind metal ions and exhibit flexible, disordered structures. The structural and functional characteristics of metallothionein I (MTL‐1) from
Caenorhabditis elegans were investigated, focusing on its behavior in both metal free (MTL‐1 Apo) and metal‐bond states with Zn2+, Cd2+, Cu2+, Hg2+, and Pb2+ divalent metal ions. Using molecular dynamics simulations and 3D modeling via AlphaFold, we characterized the flexibility and stability of MTL. The MTL‐1 Apo form displayed high flexibility, aligning with its intrinsically disordered protein (IDP) nature, with 89.3% of its structure composed of coils, bends, and turns. Metal binding significantly enhanced the protein's stability, particularly with Zn2+, Cd2+, Cu2+, and Hg2+, reducing root mean square deviation (RMSD), root mean square fluctuation (RMSF), accessible surface area (SASA) and radius of gyration (R
g) values, indicating structural compaction. Conversely, Pb2+ showed a weaker stabilizing effect, with a more dynamic and less stable structure. Structural analysis revealed that conserved cysteine residues coordinate the metal through strong thiolate interactions, with additional contributions from non‐cysteine residues, such as Glu and Lys. The study underscores the importance of incorporating intrinsically disordered protein models in MD simulations to provide deeper insights into how metallothionein's flexibility and stability vary in response to different metal ions, offering a structural perspective on their biological interactions and behavior under diverse environmental conditions. While thermodynamic aspects were not directly assessed, the results reveal consistent conformation trends across different metal coordination states.