Comparisons of Computational and Experimental Thermochemical Properties of α-Amino Acids Kabir M. Uddin, Peter L. Warburton,* and Raymond A. Poirier* Department of Chemistry, Memorial University, St. John’s, Newfoundland A1B 3X7, Canada * S Supporting Information ABSTRACT: This study provides comprehensive benchmark calculations for the thermochemical properties of the common α-amino acids. Cal- culated properties include the proton affinity, gas-phase basicity, pro- tonation entropy, ΔH° acid , ΔG° acid , and enthalpies of formation for the protonated and deprotonated α-amino acids. In order to determine the performance at various levels of theory, including density functional methods and composite methods, the calculated thermochemical properties are compared to experimental results. For all the common α-amino acids investigated, the thermochemical properties computed with the Gaussian-n theories were found to be quite consistent with each other in terms of mean absolute deviation from experiment. While all Gaussian-n theory values can serve as benchmarks, we focus on the G3MP2 values as it is the least resource-intensive of the Gaussian-n theories considered. 1. INTRODUCTION Proteins generally only contain α-amino acids while both D-α- amino acids and non-α-amino acids also occur in nature. Of the over 300 naturally occurring amino acids, the 20 common α- amino acids and their derivatives participate in diverse cellular functions and in biosynthetic reactions. The common α-amino acids are the basic monomer units from which the long polypeptide chains of proteins found in living species from bacteria to humans are formed. Understanding the thermochemical properties of the α-amino acids is of great importance in applied chemistry and the understanding of biological systems, especially through biochemical process energetics. The gas-phase protonation thermochemistry of biomolecules will provide insight into intramolecular hydrogen bonds (H-bonds) and salt-bridges that may stabilize the structures. The gas-phase protonation/ deprotonation thermochemistry of α-amino acids has been experimentally examined by the equilibrium method, 1-5 the bracketing method, 6,7 and the kinetic method. 8-11 Protonation enthalpies of amino acids are of importance in understanding proton transfer reactions in biological systems. 12 Of the com- mon protonated α-amino acids, the imidazole group of histidine, the basic group of lysine, and the guanidine group of arginine exist as resonance hybrids with the positive charge distributed over all the nitrogen atoms. 8-10 It has been shown that protonation of several amino acids in small polypeptides by electrospray ionization give highly charged ions in mass spectrometry experiments. 13,14 The intrinsic relative gas-phase acidities for α-amino acids depends on the relative strengths of the weak acid groups, -COOH and -NH 3 + : − ⇆ − + − + R COOH R COO H − ⇆ − + + + R NH R NH H 3 2 R-COOH is a far stronger acid than R-NH 3 + in the solution phase, so at a physiological pH (i.e., pH = 7.4), carboxylic groups exist almost entirely as R-COO - . However, in the gas phase, this order of acidity is reversed and carboxylic groups exist in the R-COOH form. Thermodynamic properties such as the gas-phase basicity (GB), proton affinity (PA), ΔG° acid , and enthalpy of formation for amino acids have been computed using various methods. 15-18 In addition, the comparison of experimental gas-phase IR spectra to calculated IR spectra using density functional theory (DFT) has been performed for several protonated and deprotonated amino acids. 19 In another recent work, certain thermochemical properties of glycine, alanine, valine, leucine, isoleucine, and proline were computed at the G3MP2B3 level. 20 The gas-phase basicity (GB) and proton affinity (PA) of a molecule may be affected through intramolecular effects, substituent effects, and electronic and steric interactions. Experimental studies have investigated these effects. 21-24 The study of the gas-phase zwitterionic structure of α-amino acids is of fundamental importance as shown in Scheme 1. A number of factors are involved in the stability of the zwitterionic form of an amino acid as a function of the side chain. The gas-phase basicity (-ΔG of protonation) and proton affinity (-ΔH of protonation) are defined for the protonation reaction: AH + H + → AH 2 + , where AH is the conjugate base of an acid AH 2 + (GB = -GA), and GA is the gas-phase ΔG° acid of AH 2 + . The two quantities are related by using the following equation: = + Δ°= + Δ °− ° + T S T S S H GB PA PA [ ( )] p (1) Received: November 14, 2011 Revised: February 9, 2012 Article pubs.acs.org/JPCB © XXXX American Chemical Society A dx.doi.org/10.1021/jp210948m | J. Phys. Chem. B XXXX, XXX, XXX-XXX