Fundamental Thermochemical Properties of Amino Acids: Gas-Phase and Aqueous Acidities and Gas-Phase Heats of Formation

Abstract

The gas-phase acidities of the 20 L-amino acids have been predicted at the composite G3(MP2) level. A broad range of structures of the neutral and anion were studied to determine the lowest energy conformer. Excellent agreement is found with the available experimental gas-phase deprotonation enthalpies, and the calculated values are within experimental error. We predict that tyrosine is deprotonated at the CO(2)H site. Cysteine is predicted to be deprotonated at the SH but the proton on the CO(2)H is shared with the S(-) site. Self-consistent reaction field (SCRF) calculations with the COSMO parametrization were used to predict the pK(a)'s of the non-zwitterion form in aqueous solution. The differences in the non-zwitterion pK(a) values were used to estimate the free energy difference between the zwitterion and nonzwitterion forms in solution. The heats of formation of the neutral compounds were calculated from atomization energies and isodesmic reactions to provide the first reliable set of these values in the gas phase. Further calculations were performed on five rare amino acids to predict their heats of formation, acidities, and pK(a) values.

An Experimental and Computational Study of the Gas-Phase Acidities of the Common Amino Acid Amides

“…Cysteine has been investigated theoretically and experimentally and has been found to form a thiolate ion by side chain deprotonation with a strong hydrogen bond to it from the carboxylate group. 1,21,22 In addition, Ren and co-workers have observed cysteine side chain deprotonation in experimental and computational GA studies of small cysteine-containing peptide amides. 23−26 These studies indicate that residue side chains may deprotonate in the gas phase even in the absence of a side chain carboxylic acid group.…”

A Comparison of the Effects of Amide and Acid Groups at the C-Terminus on the Collision-Induced Dissociation of Deprotonated Peptides

“…A range of structures were optimized to determine the most stable conformers. In our previous work on amino acid acidities [35][36][37] [and Bokatzian-Johnson, S. S.; Stover, M. L.; Dixon, D. A.; Cassady, C. J., unpublished results] we showed that the high level G3(MP2) correlated molecular orbital method [38] gave agreement for the acidities with the experimental values to within about ±1 kcal/mol. G3(MP2) has an additional advantage over DFT methods in terms of reliable predictions for these types of compounds because the correlated molecular orbital methods in G3(MP2) perform better in the prediction of hydrogen bond energies as well as steric non-bonded interactions than do most widely-used DFT exchange-correlation functionals.…”

“…Elimination of valine has also been observed by Jai-nhuknan [91] in a study of protonated transform growth factor (TGF) α [34][35][36][37][38][39][40][41][42][43] 3+ from TGF α (34−43), which has a C-terminal carboxylic acid group and a disulfide bond [91]. Jai-nhuknan [91] also studied the reduced form of TGF α [34][35][36][37][38][39][40][41][42][43], where the disulfide bond is cleaved; this ion did not eliminate the valine residue. This suggests that the intact disulfide bond in TGF α [34][35][36][37][38][39][40][41][42][43] facilitates a peptide ion conformation that contributes to a unique loss of an internal valine residue [91].…”

“…Jai-nhuknan [91] also studied the reduced form of TGF α [34][35][36][37][38][39][40][41][42][43], where the disulfide bond is cleaved; this ion did not eliminate the valine residue. This suggests that the intact disulfide bond in TGF α [34][35][36][37][38][39][40][41][42][43] facilitates a peptide ion conformation that contributes to a unique loss of an internal valine residue [91].…”

Gas-phase acid-base properties of 1-aminocycloalkane-1-carboxylic acids from the extended kinetic method

“…An amino acid's behavior in biological systems depends in part on their fundamental chemical properties, including their intrinsic acid/base properties [1]. Solution pK a values for all of the common protein amino acids (PAA) are readily available [1], as are the intrinsic gasphase proton affinities (PA) and gas-phase acidities (GA, DH acid ) [19,22,23,[25][26][27][28][29][30].…”