Modeling the Hydrolysis of Iron-Sulfur Clusters

Area of Science:

• Biochemistry
• Computational Chemistry
• Biophysical Chemistry

Background:

• Iron-sulfur (FeS) clusters are vital metallocoactors in numerous biological processes.
• The stability of FeS clusters in aqueous environments is crucial for their function, catalysis, and regulation.

Purpose of the Study:

• To investigate the hydrolysis mechanisms of oxidized (ferric) mononuclear FeS clusters in neutral and acidic solutions using molecular modeling.
• To elucidate the preferred reaction pathways and energy barriers for Fe-S bond cleavage.

Main Methods:

• Density Functional Theory (DFT) for electronic structure calculations, validated with Coupled Cluster (CCSD(T)) methods.
• Hybrid Quantum Mechanics/Molecular Mechanics (QM/MM) potentials and molecular dynamics simulations for solvation effects.
• Exploration of 20 reaction channels for Fe-S bond rupture.

Main Results:

• Nucleophilic substitution, involving concerted Fe-S bond breaking and formation, is the dominant hydrolysis mechanism kinetically and thermodynamically across all protonation states.
• Dissociative reactions exhibit higher energy barriers, suggesting they are less relevant in solvent-exposed FeS cluster reactivity.
• Proton transfer from water to sulfur occurs concertedly with Fe-S bond rupture in neutral solutions.

Conclusions:

• The study identifies nucleophilic substitution as the primary hydrolysis pathway for FeS clusters.
• These findings provide insights into the stability and catalytic mechanisms of various FeS clusters and proteins.