  Intramolecular ion-pair interactions yield shape and functionality to many
molecules. With proper orientation, these interactions overcome steric factors
and are responsible for the compact structures of several peptides. In this
study, we present a thermodynamic cycle based on isoelectronic and alchemical
mutation to estimate intramolecular ion-pair interaction energy. We determine
these energies for 26 benchmark molecules with common ion-pair combinations and
compare them with results obtained using intramolecular symmetry-adapted
perturbation theory. For systems with long linkers, the ion-pair energies
evaluated using both approaches deviate by less than 2.5% in vacuum phase. The
thermodynamic cycle based on density functional theory facilitates calculations
of salt-bridge interactions in model tripeptides with continuum/microsolvation
modeling, and four large peptides: 1EJG (crambin), 1BDK (bradykinin), 1L2Y (a
mini-protein with a tryptophan cage), and 1SCO (a toxin from the scorpion
venom).
