Crystal structure and conformational stability of N-acetyl-L-prolyl-L-leucinamide. Comparison between structural and thermophysical data

Molecular and crystal structure of N-acetyl-L-prolyl-L-leucinamide (NAPLA), C13H23N3O3. have been determined by single crystal diffraction study. The molecule adopts a non-usual conformation characterized by the sequence of t orsion angles phi (pro) = -79.4(5), psi (pro) = 144.0(3), phi (leu) = -108. 4(4), psi (leu) = 114.1(4)degrees. The backbone and side chain conformation s are discussed together with the pattern of intermolecular hydrogen bond i n the crystal. The cis-proline has a 'type B' geometry with C-s-C-beta-exo conformation. The Leu residue, showing a limited conformational disorder, i s in the twisted g(-)(tg(-)) conformation. Parallel calorimetric determinat ions of the melting enthalpy and entropy were accomplished and discussed on the basis of the molecular interactions occur-ring in the crystal state. T he present results are compared with the fusion thermodynamics and crystal features of other proline-containing; protected peptides recently studied a t the author's laboratories. The comparison is proved useful to justify the overall trend of fusion properties of this class of substances. Molecular mechanics calculations (AMBER) have been performed to evaluate the conforma tional energy maps of NAPLA molecule and its isomer N-acetyl-L-leucyl-L-pro linamide (NALPA). The energetically favoured conformers of the two molecule s are discussed on the basis of intramolecular interactions that stabilize more bent conformations. In the crystal state, on the contrary, the intermo lecular interactions overwhelm the intramolecular Forces. (C) 2000 Elsevier Science B.V. All rights reserved.