DPDPE

The second application of the CFTI approach described here involves calculations of the free energy differences between conformers of the linear form of the opioid pentapeptide DPDPE in aqueous solution [9, 10]. DPDPE (Tyr-D-Pen-Gly-Phe-D-Pen, where D-Pen is the D isomer of /3,/3-dimethylcysteine) and other opioids are an interesting class of biologically active peptides which exhibit a strong correlation between conformation and affinity and selectivity for different receptors. The cyclic form of DPDPE contains a disulfide bond constraint, and is a highly specific S opioid [llj. Our simulations provide information on the cost of pre-organizing the linear peptide from its stable solution structure to a cyclic-like precursor for disulfide bond formation. Such... 

The two /3-turn structures, pc and Pe are the most stable among those considered. This is in accord with the unconstrained nanosecond simulations of linear DPDPE, which converged to these conformers [14]. Because the cyclic form is relatively rigid, it is assumed that the conformation it adopts in solution is the biologically active one, responsible for its high affinity and specificity towards the 5 opioid receptor. The relatively low population of the cyclic-like structure for the linear peptide thus agrees qualitatively with the... 

Table 3. Conformational free energy simulation of linear DPDPE. Changes in free energy and its components. Units kcal/mol...

The Cyc conformer represents the structure adopted by the linear peptide prior to disulfide bond formation, while the two /3-turns are representative stable structures of linear DPDPE. The free energy differences of 4.0 kcal/mol between pc and Cyc, and 6.3 kcal/mol between pE and Cyc, reflect the cost of pre-organizing the linear peptide into a conformation conducive for disulfide bond formation. Such a conformational change is a pre-requisite for the chemical reaction of S-S bond formation to proceed. 

Y. Wang and K. Kuczera. Conformational free energy surface of the linear DPDPE peptide Cost of pre-organization for disulfide bond formation. J. Am. Chem. Soc., submitted, 1997. 

Y. Wang and K. Kuczera. Molecular dynamics simulations of cyclic and linear DPDPE Influence of the disulfide bond on peptide fiexibility. J. Phys. Chem., 100 2555-2563, 1996. 

H-Tyr-D-Ala-Pile-Asp-Val-Val-Gly-NH2 (D-Ala -deltorpliiu I) and H-Tyr-D-Ala-Plie-Glu-Val-Val-Gly-NH2 (D-Ala -deltorpliiu II) display greater 5-selectivity than DPDPE owiag to their higher 5-receptor affinity (96). These compounds both contain the same N-terminal tripeptide sequence as the. -selective dermorphins, which underscores the importance of the C-terminal tetrapeptide sequence in conferring 5-selectivity. 

Selective agonists DAMGO DPDPE, D-ala2-deltorphin II Enadoline, U-50488 ... 

Synthetic ligands Morphine DPDPE U50488H None so far... 

Synthetic agonist Morphine Codeine Fentanyl Pethidine DSTBULET DPDPE U50488H Pentazocine Oxycodone ... 

Displacement of [3H]DAMGO (p-selective) and [3H]DSLET ( -selective) from rat brain membrane binding sites. b Determined against DPDPE. c Maximal inhibition of the contractions at 10 pM. 

DPDPE—D-Pen2, D-Pen5-enkephalin DSLET—D-Ser2, Leu5-enkephalin, Thr6 DYN—Dynorphin EM—endomorphin ENK— enkephalin j8-FNA—j8-funaltrexamine, NTH—naltrindole 5 -isothiocyanate nor-BNI—Nor-binaltorphimine. 

Formation of cyclic peptides (e.g. DPDPE) less prone to enzymatic degradation by aminopeptidases... 

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