Modeling Shows that Rotation about the Peroxide O-O Bond Assists Protein and Lipid Functional Groups in...

Area of Science:

• Computational Chemistry
• Biochemistry
• Molecular Modeling

Background:

• Hydrogen peroxide (H2O2) has diverse physiological roles beyond its association with cell death.
• Understanding H2O2's biological mechanisms requires atomic-level knowledge of its interactions with biomolecules.
• Distinguishing H2O2 from water (H2O) in biological systems is critical for accurate molecular simulations.

Purpose of the Study:

• To elucidate the atomic-level interactions between hydrogen peroxide (H2O2) and biomolecular functional groups.
• To determine how protein residues and lipid groups influence H2O2's preferred conformation (rotamer).
• To develop and validate a molecular mechanics model for simulating H2O2 in biological contexts.

Main Methods:

• High-level ab initio calculations were performed to determine the lowest-energy states of isolated H2O2.
• Computational modeling was used to simulate H2O2 association with neutral and charged analogs of protein and lipid groups.
• Ab initio data were utilized to calibrate and validate a previously published molecular mechanics model for H2O2.

Main Results:

• Skew rotamers of H2O2 are favored in neutral and cationic complexes with biomolecular analogs.
• Anionic ligands exhibit significantly stronger binding with H2O2, stabilized by charge-assisted hydrogen bonds from cis rotamers.
• Biomolecular functional groups can discriminate between H2O2 and H2O based on H2O2's rotamer preference.

Conclusions:

• The conformation of H2O2 is dictated by its surrounding functional groups in biomolecules.
• This conformational preference allows biological systems to differentiate between H2O2 and H2O.
• The validated molecular mechanics model provides a valuable tool for simulating H2O2's role in biological processes.