Insights into G-Quadruplex-Hemin Dynamics Using Atomistic Simulations: Implications for Reactivity and Folding.

Area of Science:

• Biochemistry
• Molecular Biology
• Computational Chemistry

Background:

• Guanine quadruplexes (G4s) are crucial in biological processes like DNA replication and transcription.
• G4s form G4-DNAzymes with hemin, exhibiting peroxidase activity for biosensing applications.
• The atomistic details of G4-DNAzyme catalytic mechanisms remain poorly understood despite extensive research.

Purpose of the Study:

• To elucidate the atomistic details of the guanine quadruplex/hemin interaction using molecular dynamics (MD) simulations.
• To investigate the binding modes and catalytic mechanisms of G4-DNAzymes.
• To explore the role of hemin in G4 folding dynamics.

Main Methods:

• Extended explicit-solvent molecular dynamics (MD) simulations were employed.
• The interaction between guanine quadruplexes (G4s) and hemin was scrutinized.
• Simulations analyzed hemin binding sites, dynamics, and interactions with G4 folding intermediates.

Main Results:

• Hemin primarily stacks on external G-quartets but also transiently binds to loops.
• Simulations did not support catalytic mechanisms involving wobbling guanines or iron-bound water molecules.
• Results suggest the G-quartet itself, through dynamic interactions with stacked hemin, is key to H2O2-promoted catalysis.
• Hemin was observed to act as a chaperone, driving the folding of parallel-stranded G4s.

Conclusions:

• The study provides atomistic insights into G4-DNAzyme mechanisms, highlighting the G4 structure's catalytic role.
• Hemin's interaction with G4s extends beyond catalysis to influencing G4 folding.
• MD simulations offer a valuable approach to understanding complex biomolecular interactions and mechanisms.