The effects of basic site proximity on gas-phase deprotonation and hydrogen/deuterium (H/D) exchange reactions were investigated for three model dodecapeptide ions in a Fourier transform ion cyclotron resonance mass spectrometer. Each peptide contained four high basicity lysine (K) residues and eight low basicity glycine (G) residues; however, the ordering of the residues differed. In the deprotonation studies, "fully protonated" peptide ions, [M+4H]4+, where M = (KGG)4, (K2G4)2, and K4G8, were reacted with reference compounds of known basicities. Reaction efficiencies were in the order: [K4G8+4H]4+ > [(K2G4)2+4H]4+ [(KGG)4+4H]4+. The facile reaction of [K4G8+4H]4+ is consistent with this ion having the highest Coulomb energy. For gas-phase H/D exchange reactions with d4-methanol, [K4G8+4H]4+ has the fastest exchange rate and undergoes the largest number of exchanges; 22 of the 26 labile hydrogens exchanged within the timescale studied. In contrast, [(KGG)4+4H]4+ and [(K2G4)2+4H]4+ reacted more slowly, but at similar rates, with a maximum of 14 observed exchanges for both ions. Molecular dynamics calculations were conducted to gain insights into conformations. In the lowest energy structures for [(KGG)4+4H]4+ and [(K2G4)2+4H]4+, the lysine n-butylamino chains stretch out to minimize Coulomb energy; there is little or no intramolecular hydrogen bonding involving the protonated amino groups. In contrast, for [K4G8+4H]4+, the proximity of the basicity residues makes minimization of the Coulomb energy difficult; instead, the structure becomes more compact with stabilization of the protonated amino groups by extensive intramolecular hydrogen bonding to heteroatoms in the peptide backbone. The calculated structures suggest that, in the H/D exchange reactions, the compact conformation of [K4G8+4H]4+ allows stabilization of the methanol-peptide intermediate by hydrogen bonding, thus lowering the barrier to proton transfer within the complex. The diffuse conformations of [(KGG)4+4H]4+ and [(K2G4)2+4H]4+ have lower Coulomb energies and fewer avenues for hydrogen bonding with methanol, which may limit their rate and extent of exchange.