Our studies focus on using mass spectrometry techniques combined with computational methods to investigate  conformational effects on the intrinsic acid-base properties of pepides and peptide-mimicking polymers. We have measured the gas-phase acidity of a series of oligopeptides. Our results show that peptides with an acidic side-chain at the N-terminus are more acidic than the isomeric peptides with the acidic side-chain at the C-terminus by up to 10 kcal/mol. The greater acidity of the former is likely due to the helix macro-dipolar effect (for longer peptides) and efficient internal hydrogen bonding interactions (for shorter peptides) that stabilize the N-terminal acidic residues upon ionization. We have also measured the proton affinity (gas-phase basicity) of a series of short peptides containing lysine (Lys) and its unnatural homologs, including ornithine (Orn), 2,4-diaminobutanoic acid (Dab), and 2,3-diaminopropionic acid (Dap). Our results show that the peptides with a basic residue at the C-terminus have greater proton affinities than the isomeric peptides with the basic residue at the N-terminus. Computational studies show that protonated peptides with a C-terminal basic residue formed a more compact structure than the N-terminal basic residue analogs. The more compact structure allows greater stabilization of the charge via internal hydrogen-bonding. Our results also show that the proton affinity decreases as the length of the basic side-chain is shortened such that Lys-containing peptides exhibit the highest proton affinity and the Dap-containing peptides the lowest. We are in the process of examining the conformations of the peptides via computational studies. All mass spectrometry measurements were carried using a tandem-quadrupole mass spectrometer interfaced to an electrospray ion source. All computational studies were performed using the Gaussian 09 suite of programs.

Determination of the gas-phase acidity and basicity of oligopeptides by mass spectrometry

248th National Meeting (2014)

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