A comparative analysis of the two most widely used water models, SPC/E and TIP4P, was carried out. The applicability of the models for studying the conformational mobility of peptides of the insulin super family, including proinsulin and insulin-like growth factors (IGF1 and IGF2), was assessed. It was demonstrated that, in the case of both water models, the root-mean-square deviations and the gyration radii tend to exist in the anti-phase; their values only reached a plateau after 9000 ps in the case of IGF1. Additionally, it was shown that, despite maintaining a general type of insulin-like packing structure, the secondary structures were somewhat different when SPC/E and TIP4P were used. These differences could affect the overall dynamics of molecules, as well as their ability to adopt the conformation required to bind with conjugate receptors. We conclude that several, not one, water models should be used to investigate the conformational mobility of peptides.