Computational Studies of the Gas-phase Acidity of D/L-Cysteine-Containing Tetrapeptides
Poster Number
29
Introduction/Abstract
D-amino acids have been found in nearly all living organics, including humans. However, the chemistry of the D-amino acids play is largely unknown. Conversion of an amino acid from the L-form to the D-form often modifies the biological activity of the peptides, and in many cases, enhances their biological functions. Our research group has begun to study a library of oligopeptides by alternating the position and configuration of the cysteine residue along the peptide chain. In this work, the research is focused on characterizing the conformational and energetic changes in relation to the relative acidities of D/L-cysteine-containing polyalanine peptides.
Method
The gas-phase acidities were determined using a tandem quadrupole mass spectrometer by applying the extended kinetic method. The conformations and the energetics of the peptides were obtained computationally using a series of methods. A conformation search was performed using the CREST program, which gives a pool of low-energy conformations. Subsequent geometry optimizations and frequency calculations were carried out using the Hartree-Fock theory and density functional theory at the B3LYP/6-311+G(d,p) and ωB97xD/6-311+G(d,p) levels, which yields the final pool of lowest energy conformations. Theoretical gas-phase acidities were calculated based on Boltzmann averaged free energies of the final pool of conformations. Noncovalent interactions were examined using the reduced density gradient (RDG) analysis.
Results
For tetrapeptides with one cysteine (C) residue and three alanine (A) residues, the calculated gas-phase acidities at the B3LYP/6-311+G(d,p) level showed similar trend as those obtained from mass spectrometry measurements. The Gibbs free energy change (ΔG) and enthalpy change (ΔH) were used to quantify the gas-phase acidity. The experimentally ΔH values were 319.5, 320.3, 329.2, and 329.3 kcal/mol for CAAA, dCAAA, AAAC and AAAdC, respectively. Computational results were 324.1, 322.2, 329.4, and 328.1 kcal/mol for those tetrapeptides, having a small offset from mass spectrometry measurements. In general, the gas-phase acidity decreases when cysteine moves from N- to C-terminus. Tetrapeptides present the same trend as tripeptides but have more complex details. The acidity difference arises from the charged peptides instead of the neutral ones. Charged peptides appear to be more compact if the cysteine residue is on the N- or C-terminus. Charged peptides adopt more extended conformations when the cysteine residue is in the middle of the chain. RDG analysis shows that noncovalent interactions, especially hydrogen bonding, contribute significantly to the conformational stability of the peptide anions. Regardless of which position the cysteine residue residing in the peptide chain, L/D-configuration of cysteine alters the conformations in subtle ways. In order to better characterize long-range interactions, further computations will be carried out at the ωB97xD/6-311+G(d,p) level in hoping to provide a better model.
Location
Library and Learning Center, 3601 Pacific Ave., Stockton, CA 95211
Format
Poster Presentation
Computational Studies of the Gas-phase Acidity of D/L-Cysteine-Containing Tetrapeptides
Library and Learning Center, 3601 Pacific Ave., Stockton, CA 95211
D-amino acids have been found in nearly all living organics, including humans. However, the chemistry of the D-amino acids play is largely unknown. Conversion of an amino acid from the L-form to the D-form often modifies the biological activity of the peptides, and in many cases, enhances their biological functions. Our research group has begun to study a library of oligopeptides by alternating the position and configuration of the cysteine residue along the peptide chain. In this work, the research is focused on characterizing the conformational and energetic changes in relation to the relative acidities of D/L-cysteine-containing polyalanine peptides.
