Vasopressin conformation

Hundreds of analogues of both oxytocin and vasopressin have been synthesized, and the conformations of many of these have been studied (22,23). 

The energetics of Phe provide an excellent example of this phenomenon. In our molecular dynamics simulation of vasopressin, we found that Phe underwent conformational transitions between three regions of conformational space the 7 (, = -80, -1-80), a, (, i/i = -E80, -80) conformations(64). These conformations in the isolated residue, taken as the N-acetyl, N -methylamide blocked phenylalanine, are well separated energetically as can be seen in Table I. The C7 is 3.1 Kcal more stable than the 7 , and 4.7 Kcal more stable than the a,. In order to compare the relative stabilities of these phenylalanine conformations in the... 

Table I. Intra-Residue Energies of Phenylalanine in Vasopressin Minimum Energy Structures and in minimum energy conformations of Ac-Phe-NMe.

The time given is that of the molecular dynamics conformation which was minimized to give the minimum energy structure of vasopressin. The energy of the Phe fragment was calculated for these structures. 

In the enkephalin studies we began to see how theoretical techniques can be used to generate conformations of related molecules. With the results from GnRH and vasopressin we saw how flexible these molecules are and how the conformational fluctuations and dynamics of these molecules can be studied. We also saw how the relative stabilities of conformations of a molecular fragment can be influenced by conformational constraints of the whole molecule. In the following section we will present some ideas on how these calculations can be incorporated into a conformational based approach to drug design. 

Vasopressin occurs in two variations arginine-vasopressin (AVP) and lysine-vasopressin (LVP), in which Arg is replaced by Lys. The conformation of these hormones is almost identical to that of oxytocin, except that the terminal tail is con-formationally free and not held by the ring. The physiological role of the vasopressins is the regulation of water reabsorption in the renal tubules (i.e., an antidiuretic action). In high doses, they promote the contraction of arterioles and capillaries and an increase in blood pressure hence the name of these hormones. Because of their very similar structures, OT and VP overlap in a number of effects. 

Examples of the way these two entirely different approaches compliment each other are developing in conformation studies with the hormones angiotensin, oxytocin, and vasopressin. In 1964 Craig, Harfenist, and Paladini (7) published the comparative half-escape times shown in Table I in 0.01N acetic acid and another series in Table II using a different membrane less porous and not as selective as the first. Oxytocin and vasopressin are cyclic octapeptides with an S-S linkage closing the ring at the 1-6 positions (5, 6). Their size is thus limited except for the side... 

It was postulated from the comparative data in Tables I and II and other observations that angiotensin had a definite compact conformational structure even though it is a linear peptide and should be a random coil. Tritium-exchange studies (39), CD (40), and NMR evidence (41, 42) now give support to this view. NMR studies with angiotensin, oxytocin, and vasopressin thus far have not indicated conformational restriction on the benzene rings, but the thin-film dialysis data are inconsistent with any conformation in which these bulky groups are extended from the otherwise compact conformation. 

Fig. 36. Computed structures of vasopressin (A) and oxytocin (B), obtained by energy minimization, starting from the -conformation (Gibson and Scheraga, 1967b). These are the first two conformations listed in Table 22. 

The procedures and calculations described in this chapter provide considerable insight into the factors affecting the conformations of polypeptides and proteins. The computer programs for gramicidin-S, oxytocin, vasopressin, etc., can also be used for larger structures—of the size of ribonuclease and lysozyme—although the required computer time is considerably increased. 

Simulated annealing has also been applied to the conformational study of dipeptide models of Gly, Ala, and Asp pentaglycine and Leu-enkephalin [11] an analog of vasopressin [10] (3S, 4S)-statin [12] analogs of thyrotropin releasing hormone [13] and the C-peptide of Ribonuclease A [13]. 

Wuller S, Wiesner B, Loftier A et al (2004) Pharmacochaperones post-translationally enhance cell surface expression by increasing conformational stability of wild-type and mutant vasopressin V2 receptors. J Biol Chem 279 47254 7263... 

Chemical shift target functions proved their power especially in the refinement of smaller peptides as for example a vasopressin derivative.Using only traditional constraints, this cyclic peptide switched in MD simulations between two conformations. h chemical shift constraints forced the structure into a single conformation that not only fits the chemical shift constraints well but also satisfies the NOE constraints better than in their absence. Despite the fact that the accuracy of this type of chemical shift calculation for protons is still relatively low (about 0.25 ppm), chemical shift constraints can significantly reduce the conformational space allowed for the structures. 

A. T, Hagler, D. J. Osguthorpe, P. Dauber-Osguthorpe, and J. C. Hempel, Science, 227,1309 (1985). Dynamics and Conformational Energetics of a Peptide Hormone Vasopressin. 

The synthesis and transport of vasopressin depend on the conformation of the preprohormone. In particular, VP-neurophysin binds vasopressin and is critical to the correct processing, transport, and storage of vasopressin. Genetic mutations in either the signal peptide or VP-neurophysin give rise to central diabetes insipidus. 

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