A model correlating peptide helicity and deprotonated D/L-cysteine residue in the gas-phase
Poster Number
17B
Faculty Mentor Name
Jianhua Ren
Format
Poster Presentation
Research or Creativity Area
Natural Sciences
Abstract
During the course of investigating conformational and chirality effects on the gas-phase acidities of cysteine-polyalanine peptides, we have discovered several interesting trends with respect to the position and the chirality of the cysteine residue. The acidity of the peptides is the strongest when the cysteine residue is on the N-terminus, and the acidity decreases systematically when the cysteine is moved to the C-terminus. The L-cysteine appears to be a stronger gas-phase acid then the D-cysteine when cysteine is on the N-terminus, however, the relative acidity alters when the cysteine is moved to the C-terminus. In this study, we are developing a helical peptide model to correlate the peptide helicity and the position/chirality of the deprotonated cysteine residue.
Conformational search was performed using Conformer-Rotamer Ensemble Sampling Tool (CREST), which gives a large pool of low-energy conformations. Subsequent quantum chemical calculations were performed at different levels of theory using Gaussian16 package of programs. The last step was calculated at theωB97x-D/6-311+G(d,p) level, which yielded the final pool of conformations. Theoretical gas-phase acidities were derived using an isodesmic proton transfer reaction. Dihedral angles of the peptide bonds were extracted from the lowest energy conformations of the deprotonated peptides. The dihedral angles were mapped onto a standard Ramachandran plot. The ideal alpha-helical structures were built in Spartan’14. The root-mean square deviation (RMSD) values were obtained by aligning the backbone of the lowest energy conformation with ideal alpha-helix in VMD.
Based on the results, the model of helicity represents the gas-phase acidity trend well. When the helicity score is high, the helical macrodipole effect appears stronger on the peptides causing the acidity value to be shifted.
Purpose
The purpose of this study is to systematically investigate the gas-phase acidities of cysteine-containing polyalanines using computational and experimental methods. The results can be further applied to understanding biochemical reactions and drug designs.
Results
One concept called cysteine position coordinate was defined to normalize the relative position of the cysteine residue on the peptide chain. The position coordinate was calculated as the cysteine residue number minus one divided by the peptide length minus one. When the cysteine residue was on the N-terminus, the middle of the peptide chain, and the C-terminus, the position coordinate was calculated to be0.0, 0.5, and 1.0, respectively.
The peptide model was constructed based on the alignment of the carbonyl groups. Each carbonyl group was modeled as a unit vector pointing from the carbon to the oxygen. The dot product of all unit vectors were considered to be the raw carbonyl group alignment score. To unify the peptides with various lengths, the raw alignment score was divided by the alignment score of an ideal alpha-helical structure of the same sequence, resulting in a normalized carbonyl group alignment score to describe the helicity. Lowest energy conformations presented dihedral angles at the random coil region on the Ramachandran plot, except when the cysteine residue was placed on the N-terminus. If an L-cysteine was on the N-terminus, the adjacent peptide bond adopted right-handed alpha-helical angles. If a D-cysteine residue was on the N-terminus, the dihedral angles changed to that of the beta-sheets. Other dihedral angles were shown as random coils. When the peptides were elongated, the carbonyl group alignment score generally decreased as the cysteine position coordinate was increased, meaning that the cysteine was moved from the N- to the C-terminus. If the cysteine’s position was fixed, the carbonyl group alignment value first increased and then decreased with the increase of the peptide length. As for the cysteine configurational factor, L-cysteine containing peptides tended to have higher carbonyl group alignment values than those of the D-cysteine containing peptides.
Significance
Lots of enzyme active sites have cysteine residues and the acidity of these cysteine residues play an important role in enzyme activity. Our model peptides can mimic those active sites and help us study the nature of complex peptides. Our fundamental study can be further extended to biochemical and biological systems.
Location
University of the Pacific, DeRosa University Center
Start Date
24-4-2026 11:00 AM
End Date
24-4-2026 2:00 PM
A model correlating peptide helicity and deprotonated D/L-cysteine residue in the gas-phase
University of the Pacific, DeRosa University Center
During the course of investigating conformational and chirality effects on the gas-phase acidities of cysteine-polyalanine peptides, we have discovered several interesting trends with respect to the position and the chirality of the cysteine residue. The acidity of the peptides is the strongest when the cysteine residue is on the N-terminus, and the acidity decreases systematically when the cysteine is moved to the C-terminus. The L-cysteine appears to be a stronger gas-phase acid then the D-cysteine when cysteine is on the N-terminus, however, the relative acidity alters when the cysteine is moved to the C-terminus. In this study, we are developing a helical peptide model to correlate the peptide helicity and the position/chirality of the deprotonated cysteine residue.
Conformational search was performed using Conformer-Rotamer Ensemble Sampling Tool (CREST), which gives a large pool of low-energy conformations. Subsequent quantum chemical calculations were performed at different levels of theory using Gaussian16 package of programs. The last step was calculated at theωB97x-D/6-311+G(d,p) level, which yielded the final pool of conformations. Theoretical gas-phase acidities were derived using an isodesmic proton transfer reaction. Dihedral angles of the peptide bonds were extracted from the lowest energy conformations of the deprotonated peptides. The dihedral angles were mapped onto a standard Ramachandran plot. The ideal alpha-helical structures were built in Spartan’14. The root-mean square deviation (RMSD) values were obtained by aligning the backbone of the lowest energy conformation with ideal alpha-helix in VMD.
Based on the results, the model of helicity represents the gas-phase acidity trend well. When the helicity score is high, the helical macrodipole effect appears stronger on the peptides causing the acidity value to be shifted.
