Parameterization of the proline analogue Aze (azetidine-2-carboxylic acid) for molecular dynamics simulations and evaluation of its effect on homo-pentapeptide conformations

We have parameterized and evaluated the proline homologue Aze (azetidine-2-carboxylic acid) for the gromos56a3 force-field for use in molecular dynamics simulations using GROMACS. Using bi-phasic cyclohexane/water simulation systems and homo-pentapeptides, we measured the Aze solute interaction potential energies, ability to hydrogen bond with water, and overall compaction, for comparison to Pro, Gly, and Lys. Compared to Pro, Aze has a slightly higher H-bonding potential, and stronger electrostatic but weaker non-electrostatic interactions with water. The 20-ns simulations revealed the preferential positioning of Aze and Pro at the interface of the water and cyclohexane layers, with Aze spending more time in the aqueous layer. We also demonstrated through simulations of the homo-pentapeptides that Aze has a greater propensity than Pro to undergo trans→cis peptide bond isomerization, which results in a severe 180° bend in the polypeptide chain. The results provide evidence for the hypothesis that the misincorporation of Aze within proline-rich regions of proteins could disrupt the formation of poly-proline type II structures and compromise events such as recognition and binding by SH3-domains.

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► Aze (azetidine-2-carboxylic acid) is a toxic homologue of Pro (2-carboxypyrrolidine).
► Aze was parameterized for the gromos56a3 force-field in GROMACS.
► In homo-pentapeptides, Aze increases propensity of peptide bond to undergo trans→cis isomerization compared to Pro.
► This isomerization causes a nearly 180°-bend in the polypeptide chain and its compaction.
► Aze parameterization will enable investigations of effects of Aze–Pro substitutions on poly-proline type II conformation within proteins.