Basis set, level, and continuum solvation effects on the stability of a synthetic dipeptide: PIDOTIMOD

The conformational preferences of PIDOTIMOD, namely 3-(5-oxo-L-propyl)-L-th iazolidin-4-carboxyl acid, a synthetic dipeptide showing a beneficial influ ence on some immune functions both in mammalians and in humans, have been s earched by varying two of its rotatable dihedral angles, preliminary result s in vacuo on the conjugated basis used the STO-3G* basis set. At that leve l, the phi(1), phi(3) potential energy surfaces for phi(2) equal either to 0 degrees or 180 degrees were also explored in the flexible rotor approxima tion. When phi(2) is equal to 180 degrees, however, for 120 degrees less th an or equal to phi(1) less than or equal to 260 degrees the nitrogen proton shuttling to the adjacent carboxyl anion was observed; therefore, a constr aint had to be imposed on the N-H bond distance to prevent this artifact. I n the phi(2) = 180 degrees potential energy surface computed employing the 6-31G* basis set, in fact, the proton remained on the N atom everywhere. Th e proton transfer was then studied in vacuo at the HF/6-31G* and 6-31+G* le vels and, in contrast to the STO-3G* spontaneous process, the energy barrie r turned out to be about 13 kcal/mol. The energy of selected conformers cor responding to minima on the potential energy surface in vacuo was computed with the inclusion of correlation corrections at the MP2 level and in aqueo us solution in the polarizable continuum model framework. A sensitive influ ence of correlation effects on the trans forms with intramolecular H-bonds is observed, while the solvent stabilizes the conformer with the polar grou ps widely exposed to it. The energy gap among the cis rotamers amounts to s imilar to 3 kcal/mol, with the energy of the most stable of them in-vacuo s imilar to 6 kcal/mol higher than that of the trans conformers. The most sta ble cis structure becomes the second most populated conformer in aqueous so lution at the MP2 level, though all the cis conformers are sharply stabiliz ed in solution. A preliminary study in vacuo of the trans-cis interconversi on was also carried out.