Met-enkephalin conformation

As mentioned above, the total energy is an index of the conformational stability of peptides in solvent. Table 3-10 gives Eg, A/is, and A t for conformations 1 and 4 of Met-enkephalin. Conformation 1 has intramolecular hydrogen bonds. Conformation 4 is almost fully extended and has no intramolecular hydrogen bonds. Aixs,w, AiJ,s,u, and A s.e denote the solvation free energies in water, methanol, and ethanol, respectively. fi x.W) t,m> t,e denote the total energies in water. 

Figure 13. Plot of met-enkephalin conformation (in stereo). Giobai minimum energy of -50.01 kcal/mol using the RRIGS model for hydration.

The influence of chain length and side-chain modifications of ACTH-derived peptides on active avoidance behaviour in rats will be discussed. H-Met(02)-Glu-His--Phe-D-Lys-Phe-OH (Org 2766) emerged from these studies as an orally active peptide with an increased potency and selectivity of action. Physico-chemical data (from the literature) on the reference peptide ACTH--(4-10) did not point to a preferred conformation in solution, whereas in the crystalline state an antiparallel 3-pleated sheet structure was found. At the receptor site we suggested an a-helical conformation in which the Phe and Met residues are close together. Additional support for this suggestion came from the behavioural activity of [des-Tyr", Met ]enkephalin and of cyclo--(-Phe-Met-cAhx-), eAhx merely serving as a spacer. 

Fig. 1. Small peptides can assume multiple conformational states in the solid state. The hydrogen-bonding patterns for two crystalline forms of Met-enkephalin (A and B) and a potent derivative of Met-enkephalin as determined by X-ray crystallography are illustrated (Smith and Griffin, 1978 Stezowski et al., 1985 Griffin et al., 1986). The conformations are antiparallel /3 pleated sheet (A), type I /3 turn (B), and type II j8 turn (C).

Figure 27 Illustration of random starting conformations of Met-enkephalin (indicated by the numbers 1 to 18) and the global minimum (indicated by 0), which was reached from 13 of the 18 starting conformations.177 In a subsequent variation of the procedure,189 all 18 starting conformations converged to the same global minimum.

Figure 30 Stereo views of some conformations of Met-enkephalin along a conformational pathway in the electrostatically driven Monte Carlo procedure during a folding simulation, starting from a randomly generated structure. The structure in (d)191 is the same as that in Figure 23.

This procedure has been tested on Met-enkephalin,194-196 and it led to a lowest-energy conformation similar to that found by the other methods discussed here however, because of the inclusion of conformational entropy in this procedure,196 a conformation higher in energy but lower in free energy was also obtained. 

Figure 36 Progress of the MCM procedure, starting from two different initial randomly chosen conformations of Met-enkephalin (a and b). In each of the two cases, the ECEPP energy and the root-mean-square deviation with respect to the global minimum-energy structure are shown.222...

K. A. Olszewski, L. Piela, and H. A. Scheraga, J. Phys. Chem. 96,4672 (1992). Mean-Field Theory as a Tool for Intramolecular Conformational Optimization. I. Tests on Terminally-Blocked Alanine and Met-enkephalin. 

Energy transfer experiments by spectrofluorimetry enable an estimate to be made of the Tyr-Trp separation in Trp4-Met-enkephalin, an analog that is about a quarter as active as the parent in the MVD test. The value obtained (—10 A) is close to the phenol-phenyl separation in a potent oripavine derivative in support of peptide /3rbend conformations.067 ... 

Quantum mechanical calculations have been applied to opioid peptides in attempts to identify low-energy conformers and to study their relationships to rigid opioids. Of the 52 conformations reported for met-enkephalin,(205) the lowest-energy structures (those with AE = 2.5 kcal/mol) were found to have... 

We extended the use of our program Anneal-Conformer and the Amber force field for conformation searching of peptides [5]. We were also able to efficiently locate several new families of active conformations of Met-enkephalin [6]. Similar studies of Met-enkephalin Kawai [7] on a simplified ECEPP energy surface also demonstrated the efficiency of simulated annealing. 

It is demonstrated that polymorphs of the crystalline biologically-active peptides, Leu- and Met-enkephalins, are also easily distinguished by NMR on the basis of displacements of chemical shifts [80, 81]. Recently, we showed that high resolution solid-state NMR approach is a very useful mean to delineate local conformational change from a-helix to j8-sheet associated with fibril formation of selectively C-labeled human calcitonin [82]. In addition, we also demonstrated that chemical shift data were very conveniently used as an initial constraints to construct three-dimensional structures of Leu-enkephalin, based on accurately determined interatomic distances by REDOR [6, 83]. This aspect of work was already described in Chapter 2. 

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