Date of Award

2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (Ph.D.)

Department

Pharmaceutical and Chemical Sciences

First Advisor

Jianhua Ren

First Committee Member

Michael McCallum

Second Committee Member

Miki S. Park

Third Committee Member

Jerry Tsai

Fourth Committee Member

Qinliang Zhao

Abstract

This dissertation presents a comprehensive study of the peptides of interest to deeper understand the gas-phase acid-base properties in relation to their conformations and chirality. In the first part of the study, two pairs of alanine (A)-based isomeric peptides consisting of a basic probe, lysine (Lys) or 2,3-diaminopropionic acid (Dap), were investigated to understand the nature of the enhanced basicity when the basic probe was moved from the N-terminus to the C-terminus. In the second part of the study, alanine-based peptides containing a cysteine (C) as the acidic probe were investigated to understand the chirality effects on the gas-phase acidity by altering the chiral centers systemically. Previous studies by mass spectrometry showed that the peptides ALys and AADap have had remarkably higher proton affinity (PA) compared to their isomeric counterparts LysA and DapAA. In this work, conformations, energetics, and molecular properties of the peptide systems have been thoroughly characterized through infrared multiple photon dissociation (IRMPD) spectroscopy and quantum chemical computations utilizing a set of molecular modeling tools. The molecular properties include charge distribution, dipole moment, torsional strain, hydrogen bonding, and non-covalent interaction. Computational studies yielded the lowest energy conformations along with their theoretical infrared (IR) spectra for each of the peptide systems. The resulting theoretical proton affinities are in excellent agreement with experiments. The results also suggest that the relative stability of the protonated peptides is the main source of the difference in the gas-phase basicity between the isomeric peptides. Structurally representative conformations for the protonated peptides were identified by matching the theoretical IR spectra to the corresponding IRMPD spectra. The band features of the IRMPD spectra were analyzed in detail by vibrational mode decomposition. The N-probe peptide ions, LysAH+ and DapAAH+, adopt diverse backbone geometries and intramolecular hydrogen bonding networks, and rely heavily on the hydrogen bonds for conformational stabilization. In contrast, the C-probe peptide ions, ALysH+ and AADapH+, adopt helical conformations, and benefit from the interaction between the helix macrodipole and the charged NH3+ group. The low torsional strain on the Lys sidechain contributes significantly to the conformational stability for ALysH+ than for LysAH+.

The chirality of each residue in CAAA and Ac-CAAA (Ac represents the acetyl group) alters from the L- to the D-form systematically to generate two series of peptides. Qualitative comparison of the gas-phase acidity was achieved through mass spectrometry measurements using the Cooks’ kinetic method. The following two acidity ladders from the most acidic to the least acidic were obtained: CAAdA > CAdAA ~ CAAA > dCAAA > CdAAA, and Ac-dCAAA > Ac-CAAdA > Ac-CAAA > Ac-CAdAA > Ac-CdAAA, where the superscript-d in front of the amino acid symbol indicates the D-form of that residue. In both non-acetylated and acetylated peptides, the gas-phase acidity increases as the D-alanine moves further away from the N-terminal acidic probe cysteine. Inversion of the cysteine residue from the L- to the D-form reduces the gas-phase acidity of the non-acetylated peptide and enhances the gas-phase acidity of the acetylated one. Overall, the change in the gas-phase acidity is likely due to the conformational reorganization in the deprotonated peptides upon chiral inversion.

Pages

282

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