Journal of Computer-Aided Molecular Design, 2 (1988) 281-309 ESCOM 281 J-CAMD 050 Molecular mechanics calculations on deaminooxytocin and on deamino-arginine-vasopressin and its analogues A. Liwo, A. Tempczyk and Z. Grzonka* Institute of Chemistry, University of Gdansk, ul. Sobieskiego 18, 80-952 Gdansk, Poland Received 7 March 1988 Accepted 10 June 1988 Key words." Molecular mechanics; Conformational analysis; Neurohypophyseal hormones; Oxytocin and vasopressin analogues; Cyclic moiety SUMMARY The backbone conformations of the cyclic moieties of 1-[fl-mercaptopropionic acid]-oxytocin ([Mpal] - OT), [l-,8-mercaptopropionic acid]-arginine-vasopressin ([Mpal]-AVP), [1-(fl'-mercapto-fl,/?-cyclopenta- methylene)propionic acid]-arginine-vasopressin ([Cppr]-AVP), and [l-thiosalicylic acid]-arginine-vasopres- sin ([Ths']-AVP) have been analyzed by means of molecular mechanics. In these calculations, the side chains were simulated by pseudoatoms. For the three last compounds, the calculations were also performed on the whole molecules, in order to shed light on the differences in their biological activity. Their starting conforma- tions were obtained by attaching the acyclic tail and side chains to the lowest energy conformations of the cyclic parts. In the case of [Thsr]-AVP, however, other starting conformations were also examined, which were obtained by attaching the planar benzene ring to the lowest energy conformations of [Mpal]-AVP. In the calculations, all the degrees of freedom were relaxed and Weiner's force field was used, the parameters re- quired for the benzene parts of [Ths']-AVP being determined from the experimental data available, as well as from the results of molecular dynamics calculations on the model compounds. The lowest energy confor- mations of [Mpal]-AVP and [Cpp'J-AVP are similar, while [Thsl]-AVP differs from them near the disulphide region, due to the presence of a planar benzene ring. Interactions involving the charged guanidine group of arginine make, in each case, an important contribution to the conformational energy. A model description of the shapes of the oxytocin and vasopressin ring has been proposed, which is based on the cyclohexane ge- ometry. This description is in good correlation with the energetics of the conformations corresponding to dif- ferent shapes. INTRODUCTION Many conformational studies have been carried out on vasopressin and oxytocin themselves and on their derivatives, in which both theoretical and experimental methods have been used [1,2]. Because of the high complexity of the compounds under study, the theoretical methods are limit- * To whom correspondence should be addressed. 0920-654X/89/$3.50 9 ESCOM Science Publishers B.V.