Assessment of the bioactive conformation of the vasoactive intestinal peptide by computational methods

In the present work, we report the results of a computational study aimed at assessing the structural features of the bioactive conformation of the vasoactive intestinal peptide (VIP). Based on previous structure-activity studies the present work reports the results of a comparative analysis of the conformational profiles of the segments 1-11 of the native peptide, two VIP antagonists and two inactive analogs. All these analogs exhibit the same sequence as VIP at C-terminus and only differ in some of the amino acids of the N-terminus. Analogs selected for the present study include VIP(7-28) fused to neurotensin (6-11) (Met-hydrid) and [Ac-Tyr¹, D-Phe²]-VIP (both antagonists) and [Ala³]-VIP and [Ala⁶]-VIP (two inactive analogs). The conformational space of the five peptides was thoroughly explored using simulated annealing in an iterative fashion as sampling technique. The bioactive conformation was selected from pairwise cross-comparisons between each of the unique low energy conformations found for VIP(1-11) and each of the different analogs, within a 3 kcal/mol threshold in regard of the respective lowest energy conformation characterized.