Structures and conformational energies of amino acids in the zwitterionic, hydrogen-bonded state

Ab initio methods have been used to calculate relative energies for all side chain rotamers of the hydrophobic amino acids l-valine, l-leucine, l-isoleucine and l-norvaline, with supplementary calculations for glycine, l-alanine, l-serine and S-fluoroglycine. The amino acids were in the zwitterionic state, which was stabilized by explicit inclusion of three hydrogen bond donors and three hydrogen bond acceptors, thus forming complexes of seven molecules. Each complex was optimized at the HF/6-311++G∗∗ and B3LYP/6-311++G∗∗ levels of theory. The results are in excellent agreement with observations in crystal structures. A detailed analysis shows that the lowest energy (and most frequently observed) side chain rotamers invariably have the best set of intermolecular interactions overall, and in particular the most favourable hydrogen bonds to the three acceptor molecules. If just the isolated zwitterionic amino acids are considered (with geometries fixed as in the complexes), different sets of relative energies are obtained that do not fit the crystal structure distributions. The effect of the nature of the side chains on the total interaction energy has been addressed by considering not only their inductive effect on the hydrogen bonds involving the charged amino and carboxylate groups, but also the direct interactions between the side chains and the surrounding donors and acceptors.