Receptor-ligand and other macromolecular host-guest interactions comprise a wide range of noncovalent forces, ranging from hydrogen bonding and electrostatic effects to ion-dipole and dipole-dipole interactions, charge-transfer complexation, pi-stacking, and hydrophobic effects. Since many such complexes have recently been observed by ion spray mass spectrometry, it became of interest to ascertain whether meaningful information about solution binding constants might be obtained from ion current abundances for the gas-phase noncovalent ions. To evaluate the prospects for success in a favorable case,we chose to investigate the binding of rapamycin and four synthetic analogs to the cytoplasmic receptor FKBP. Here we extend our previous studies by applying tandem mass spectrometry (MS/MS) at different collision energies to investigate the relative energetics of noncovalent binding in immunophilin-ligand complexes in the gas phase.