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

Long associated with cell death, hydrogen peroxide (H₂O₂) is now known to perform many physiological roles. Unraveling its biological mechanisms of action requires atomic-level knowledge of its association with proteins and lipids, which we address here. High-level [MP2(full)/6-311++G(3df,3pd)] ab initio calculations reveal skew rotamers as the lowest-energy states of isolated H₂O₂ (ϕ_HOOH ∼ 112°) with minimum and maximum electrostatic potentials (kcal/mol) of -24.8 (V_s,min) and 36.5 (V_s,max), respectively. Transition-state, nonpolar trans rotamers (ϕ_HOOH ∼ 180°) at 1.2 kcal/mol higher in energy are poorer H-bond acceptors (V_s,min = -16.6) than the skew rotamers, while highly polar cis rotamers (ϕ_HOOH ∼ 0°) at 7.8 kcal/mol are much better H-bond donors (V_s,max = 52.7). Modeling H₂O₂ association with neutral and charged analogs of protein residues and lipid groups (e.g., ester, phosphate, choline) reveals that skew rotamers (ϕ_HOOH = 84-122°) are favored in the neutral and cationic complexes, which display gas-phase interaction energies (E^CP, kcal/mol) of -1.5 to -18. The neutral and cationic complexes of H₂O exhibit a similar range of stabilities (E^CP ∼ -1 to -18). However, considerably higher energies (E^CP ∼ -14 to -36) are found for the H₂O₂ complexes of the anionic ligands, which are stabilized by charge-assisted H-bond donation from cis and distorted cis rotamers (ϕ_HOOH = 0-60°). H₂O is a much poorer H-bond donor (V_s,max = 33.4) than cis-H₂O₂, so its anionic complexes are significantly weaker (E^CP ∼ -11 to -20). Thus, by dictating the rotamer preference of H₂O₂, functional groups in biomolecules can discriminate between H₂O₂ and H₂O. Finally, exploiting the present ab initio data, we calibrated and validated our published molecular mechanics model for H₂O₂ (Orabi, E. A.; English, A. M. J. Chem. Theory Comput. 2018, 14, 2808-2821) to provide an important tool for simulating H₂O₂ in biology.