In 2011, the Human Proteome Project (HPP) was launched with the main goal of experimentally mapping the entire human proteome. Determining a protein’s sequence is a first step to understanding its structure and function, which are of great importance in biological, biochemical, and medical studies. The sequencing of peptides and proteins by mass spectrometry (MS) has become a major tool in proteomics research because it is a cost effective and highly reproducible analytical technique. The analysis of biomolecules by mass spectrometry requires an understanding of proton transfer reactions because the two most commonly used ionization techniques, electrospray ionization (ESI) and matrix-assisted laser desorption ionization (MALDI), involve the addition and removal of protons. The sites of proton transfer reactions can affect the fragmentation patterns of peptide ions, which consequently impacts the sequence information that can be obtained from mass spectrometry experiments. Thermodynamic values, such as the gas-phase acidity (GA or ∆Gacid), the ΔG for the deprotonation reaction AH → A- + H+, provide valuable information to help in understanding the less studied negative ion peptide fragmentation mode by mass spectrometry. The study of gas-phase proton transfer reactions provides unique insights into the structures and energetics of the peptides. Changing the protonation state can impact the hydrogen bonding in the molecule and result in decreased or increased properties such as solubility, hydrophobicity, and electrostatic interactions. By combining these experimentally obtained results with the results from high level electronic structure theory calculations, an improved understanding of the structures and energetics of polypeptides can be obtained. Herein we describe computational studies using reliable, correlated molecular orbital methods of the gas-phase properties, including acidities and heats of formation, and solution-phase acidities of amino acids (AAs) and small peptides including substituted molecules such as AA amides and phosphorylated AAs. This dissertation will focus on the prediction of fundamental thermodynamic properties of AAs and small peptides that are of interest in the area of biochemistry, proteomics, and the Human Proteome Project.