Structures of protonated arginine dimer and bradykinin investigated by density functional theory: Further support for stable gas-phase salt bridges

The gas-phase structures and energetics of both protonated arginine dimer a nd protonated bradykinin were investigated using a combination of molecular mechanics with conformational searching to identify candidate low-energy s tructures, and density functional theory for subsequent minimization and en ergy calculations. For protonated arginine dimer, a good correlation (R = 0 .88) was obtained between the molecular mechanics and EDF1 6-31+G* energies , indicating that mechanics with MMFF is suitable for finding low-energy co nformers. For this ion, the salt-bridge or ion-zwitterion form was found to be 5.7 and 7.2 kcal/mol more stable than the simple protonated or ion-mole cule form at the EDF1 6-31++G** and B3LYP 6-311++G** levels. For bradykinin , the correlation between the molecular mechanics and DFT energies was poor (R = 0.28), indicating that many low-energy structures are likely passed o ver in the mechanics conformational searching. This result suggests that st ructures of this larger peptide ion obtained using mechanics calculations a lone are not necessarily reliable. The lowest energy structure of the salt- bridge form of bradykinin is 10.6 kcal/mol lower in energy (EDF1) than the lowest energy simple protonated form at the 6-311G* level. Similarly, the a verage energy of all salt-bridge structures investigated is 13.6 kcal/mol l ower than the average of all the protonated forms investigated. To the exte nt that a sufficient number of structures are investigated, these results p rovide some additional support for the salt-bridge form of bradykinin in th e gas phase.