1 Department of Chemistry, Faculty of Science, Assiut University, Assiut 71516, Egypt.
2 Department of Chemistry and Biochemistry, Concordia University, 7141 Sherbrooke Street West, Montréal, Québec H4B 1R6, Canada.
3 Center for Research in Molecular Modeling (CERMM) and Quebec Network for Research on Protein Function, Engineering, and Applications (PROTEO), Concordia University, Montreal, Quebec H4B 1R6, Canada.

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 (?_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 (?_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 (?_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 (?_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 (?_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.