Modeling Shows that Rotation about the Peroxide O-O Bond Assists Protein and Lipid Functional Groups in Discriminating between H2O2 and H2O.

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 (ϕHOOH ∼ 112°) with minimum and maximum electrostatic potentials (kcal/mol) of -24.8 (Vs,min) and 36.5 (Vs,max), respectively. Transition-state, nonpolar trans rotamers (ϕHOOH ∼ 180°) at 1.2 kcal/mol higher in energy are poorer H-bond acceptors (Vs,min = -16.6) than the skew rotamers, while highly polar cis rotamers (ϕHOOH ∼ 0°) at 7.8 kcal/mol are much better H-bond donors (Vs,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 (ϕHOOH = 84-122°) are favored in the neutral and cationic complexes, which display gas-phase interaction energies (ECP, kcal/mol) of -1.5 to -18. The neutral and cationic complexes of H2O exhibit a similar range of stabilities (ECP ∼ -1 to -18). However, considerably higher energies (ECP ∼ -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 (ϕHOOH = 0-60°). H2O is a much poorer H-bond donor (Vs,max = 33.4) than cis-H2O2, so its anionic complexes are significantly weaker (ECP ∼ -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.