Acta Chini. Slov. 2002, 49, 55-65. 55 COMPARATIVE CONFORMATIONAL STUDY OF CHEMOTACTIC PEPTIDES formyl-Met-Leu-Phe-OMe AND formyl-Met-Acc5-Phe-OMe. Youssef Wazady Laboratoire de recherche, Ecole Supérieur de Technologie, BP 8012 Oasis, Route d'El Jadida, Km 7, Casablanca-Maroc Chakib Ameziane Hassani Département de chimie, faculté des sciences et techniques Fes sais, Université Sidi Mohamed Ben Abdellah BP 2202, Fes-Maroc Mahjoub Lakhdar, Aziz Ezzamarty Département de chimie, Faculté des Sciences BP 5366 Maârif/ Casablanca-Maroc Received 16-05-2001 Abstract The chemotactic peptides formyl-Met-Leu-Phe-OMe and formyl-Met-Acc5-Phe-OMe (Acc5 is the oc-oc disubstituted amino acid 1-aminocyclopentane-l-carboxylic acid) were studied by the theoretical method PEPSEA in order to investigate the proper peptide backbone conformation that is biologically active. This study shows that the parent peptide formyl-Met-Leu-Phe-OMe has a flexible structure, and that the other conformationally constrained peptide has a tendency to form the ß turn structure. It also gives evidence against the hypothesis proposing the importance of formyl group in the interaction with the receptor. Introduction Chemotaxis is defined as a reaction by which the direction of locomotion of cells is determined by substances, called chemotactic agents, in their environment. These substances of different origin are responsible for the accumulation of leukocytes, particularly neutrophils in areas of inflammation. The discovery that A7-formyl peptides are chemoattractants for these cells has led to the investigation of structural requirements for peptide-receptor interaction. ' The formyl-Met-Leu-Phe-OH and its synthetic analogue formyl-Met-Leu-Phe-OMe emerged as the prototypic chemotactic tripeptides. Several studies have been carried out in order to better understand this tripeptide. The influence of terminal groups has been studied, and it has been demonstrated that the esterification of the C-terminal carboxylic acid group does not result in loss of biological activity of molecule. However, the replacement of the A^-terminal formyl group by tert-butyloxycarbonyl group (Boc) induces a dramatic loss of activity. C. H. Ameziane, M. Lakhder, A. Ezzamarty, Y. Wazady: Comparative conformational study... 56 Acta Chini. Slov. 2002, 49, 55-65. In an effort to produce synthetic agents that are more active and more resistant to enzymatic hydrolysis, several modifications have been undertaken. " The replacement of the Met by the thiomethionine residue (Met ) induces a dramatic loss of activity. The comparative study of the formyl-Met-Leu-Phe-OMe and formyl-Met -Leu-Phe-OMe has shown that an active chemotactic peptide must have the formyl group free of any intramolecular interaction in order to be available for the formation of the complex with the receptor. Among the modifications made on the tripeptide formyl-Met-Leu-Phe-OMe, we can quote the substitution of the Leu residue by the a,a-disubstituted amino acids such as Acc5 (1- aminocyclopentane-1-carboxylic acid). H\ /H H\ /H N N JOH ÛH Leu ° Acc5 ° Figure 1. Structures of amino acids Leu and Acc5. This amino acid was the subject of a considerable number of conformational II 17 studies.11'1" The presence of a a,a-disubstituted carbon atom in this amino acid confers upon it the property to have a considerable steric effect, which can then impose significant constraints on the orientation of the peptide backbone. The use of this residue in a given peptide will facilitate the determination of the conformation adopted during the interaction with the receptor, as well as the search of pharmacophore groups. To measure the activity of formyl-Met-Leu-Phe-OMe and formyl-Met-Acc5-Phe-OMe, their ability to induce the release of lysosomal enzymes in rabbit neutrophils was 1 ~k used. These measurements, which were undertaken by Sukumar's group, showed that these two peptides are active (chemotactic peptides). C. H. Ameziane, M. Lakhder, A. Ezzamarty, Y. Wazady: Comparative conformational study... Acta Chini. Slov. 2002, 49, 55-65. 57 H O H O \ H O Me Me formyl-Met-Leu-Phe-OMe formyl-Met-Acc5-Phe-OMe Figure. 2. Structures of formyl-Met-Leu-Phe-OMe and formyl-Met-Acc5-Phe-OMe. The conformational study, that was carried out by H-NMR, IR, and X-rays on these two peptides and other formyl-Met-Leu-Phe-OMe analogs containing other a,a-disubstituted amino acids, has not been able to give a common structure that can explain the biological activity of the chemotactic peptides. " This can be explained by the fact that the analyses by the various experimental methods are carried out in media and environments that are different to those in which these peptides exert their biological function. Consequently, the resulting structures are not necessarily the active structures. Using a theoretical method, the present article is interested in the comparative conformational analysis of formyl-Met-Leu-Phe-OMe and formyl-Met-Acc5-Phe-OMe. The main objective of this study is to find the active conformation of chemotactic peptides. Method The method used in this study is called PEPSEA (PEPtidic SEArch). It was developed in the structural chemistry laboratory of the Sherbrooke University. This approach is based on the fact that the structural, thermodynamic and statistical properties of a molecular system can be deduced only from a population presenting its conformational space. The principle of PEPSEA consists of generating a population of conformations that characterize a particular peptidic sequence. Rather than striving for global minima, populations of conformers are randomly generated, and their energy is minimized. A statistical analysis can be applied upon these populations to deduce the thermodynamic and structural properties of the peptide under investigation. This new approach is applied with the PEPSEA program. C. H. Ameziane, M. Lakhder, A. Ezzamarty, Y. Wazady: Comparative conformational study... 58 Acta Chini. Slov. 2002, 49, 55-65. The force field used by the PEPSEA program to compute the conformational energy is ECEPP/2 "Empirical Calculation Energy Program for Peptide". This force field uses rigid geometry to represent the amino acid residues of a polypeptidic chain. The conformational energy function is given by the sum of the electrostatic term Eeie, 12-6 Lennard-Jones term Eu, and hydrogen-bond term Ehb for all pairs of atoms in the molecule together with the torsion term Etor for all torsion angles. ECOnf = Eeie + Elj + Ehb + Etor The PEPSEA program uses the specific parameters of each residue (atomic coordinates, geometrical and energy parameters...) to describe the geometry of a peptidic molecule. The force field ECEPP/2 possesses the parameters of 26 amino acid residues and of terminal protecting groups commonly found in proteins. However, the Acc5 residue is not included in the database, so it is necessary to calculate its parameters and integrate them in the force field ECEPP/2. The atomic partial charges for this particular residue are computed by CNDO calculation. It is worth noting that the dielectric constant used by PEPSEA is D= 2 (different of that in vacuous). According to Scheraga and al. this effective dielectric constant D = 2 is equivalent to the experimental dielectric constant (set between 4 and 8) similar to that of proteins in polar medium. As all endogenous peptides, the tripeptides under investigation in this study are constituted by the sequence of amino acids, all in L configuration. Experimental The PEPSEA program described above carried out the conformational search and the localization of the most stable minima. For each of the two considered peptides, 6000 conformers were randomly generated and energy minimized to the closest minima. During this generation process, all torsion angles are allowed to vary except those of the amide bonds; co (Met), co (Leu) or co (Acc5) which are fixed at 180°. For each peptide, the first 100 conformers of lower conformational energies were submitted to a second energy minimization allowing all dihedral angles to be modified. The hessian matrix was calculated and the free energy was evaluated. The resulting population of conformers was sorted by increasing value of the free energies. C. H. Ameziane, M. Lakhder, A. Ezzamarty, Y. Wazady: Comparative conformational study... Acta Chini. Slov. 2002, 49, 55-65. 59 The calculations of energy and minimization were performed on HP Apollo 9000 series 700, model 715 workstation at the higher school of technology of Casablanca. Results For the evaluation of the minimization efficiency, we have studied the energy distribution of 6000 minimized conformers of tripeptides formy-Met-Leu-Phe-OMe and formyl-Met-Acc5-Phe-OMe. The next figure represents these distributions. 800- 600- o § 400- ct fcn 200- formyl-Met-Leu-Phe-OMe lllli___,. 10 20 30 40 50 Relative energy (Kcal/mol) 60 500- 400- g 300- CT £200- 100- formyl-Met-Acc5-Phe-OMe Uli,.....,¦¦ 60 10 20 30 40 50 Relative energy (Kcal/mol) Figure 3. Energy distribution of minimized conformers of tripeptides formy-Met-Leu-Phe-OMe and formyl-Met-Acc5-Phe-OMe. C. H. Ameziane, M. Lakhder, A. Ezzamarty, Y. Wazady: Comparative conformational study... 60 Acta Chini. Slov. 2002, 49, 55-65. Table 1. Conformational characteristics of formyl-Met Conf. Relative free energy AG b (kcal/mol) Relative conformational energy AE c (kcal/mol) l 0.00 0.00 2 0.34 0.07 3 0.54 0.38 4 0.69 0.60 5 1.07 0.39 6 1.11 1.41 7 1.23 1.00 8 1.58 1.37 9 1.69 2.37 10 1.70 0.92 11 1.71 1.40 12 1.73 1.73 13 1.80 0.99 14 1.83 1.53 15 1.84 1.53 16 1.87 1.43 17 1.89 1.83 18 1.90 0.66 19 1.92 2.52 20 1.93 2.11 4-Met-] Leu-Phe-OMe a formyl Met Leu Phe CO NH CO NH CO NH CO NH CO NH CO NH CO NH CO NH CO NH CO NH CO NH CO NH CO NH CO NH CO CO NH NH CO CO NH NH a. First 20 minimum energy conformations are listed. b. AC= G - C0. Go is the free energy of the conformation in order that £ = C. AE = E - E0. E0 (formyl-Met-Leu-Phe-OMe) = - 4.22 kcal/mol. Er, 'able 2. Conformational characteristics of formy Conf. Relative free energy AGb (kcal/mol) Relative conformational energy AEc (kcal/mol) l -0,47 2,1 2 -0,43 1,46 3 -0,3 1,09 4 -0,17 1,8 5 -0,14 1,86 6 -0,13 0,31 7 -0,13 1,86 8 -0,13 1,86 9 0.00 0.00 10 0,37 2,39 11 0,46 2,13 12 0,46 2,13 13 0,47 2,1 14 0,52 1,9 15 0,63 1,95 16 0,67 3,07 17 0,68 2,66 18 0,69 2,19 19 0,72 2,32 20 0,76 1,14 L-Met-Acc5-Phe-OMe a formyl Met Acc5 Phe CO NH CO NH CO NH CO NH CO NH CO NH CO NH CO NH CO NH CO NH CO NH CO NH CO NH CO NH CO NH CO NH a. First 20 minimum energy conformations are listed. b. AC= G - C0. Go is the free energy of the conformation in order that £ = c. AE = E - E0. E0 (formyl-Met-Acc5-Phe-OMe) = - 4.48 kcal/mol. E0. C. H. Ameziane, M. Lakhder, A. Ezzamarty, Y. Wazady: Comparative conformational study... Acta Chini. Slov. 2002, 49, 55-65. 61 We can observe that these graphs have an alone distribution in form of bell "gaussian form". This remark confirms the good progress of the minimization and that the variable torsion angles have been well chosen. Table 3. List of torsion angles for formyl-Met-Leu-Phe-OMe. f ormyl Met Leu Phe OMe AG e ? V o X X X x4 ? V o X X X x4 ? V o X X e 1 0 .00 179 -157 131 177 179 Ill 173 -60 -79 87 177 -179 63 -68 59 -70 144 -175 -63 107 58 2 0 .34 179 -156 131 180 179 111 173 -60 -81 89 180 179 61 -68 58 -72 -25 173 -63 107 -57 3 0 .54 -178 -66 -32 178 -171 173 179 60 -62 -38 -176 176 62 -67 -61 -100 25 -170 -52 104 -63 4 0 .69 -178 -66 -34 177 -172 174 179 -60 -78 81 178 -176 65 51 179 -75 147 -176 -61 -70 178 5 1 .07 179 -157 134 -179 179 170 172 59 -82 79 178 -57 173 -178 70 -63 136 -174 -65 -71 58 6 1 .11 -178 -79 75 178 -66 -178 -179 -59 -79 -27 179 -58 172 -59 70 -143 159 -178 -57 -77 179 7 1 .23 -179 -73 133 -175 -167 175 179 -60 -67 -53 -175 175 61 172 177 -89 131 -174 -55 -71 -62 8 1 .58 -179 -76 -30 179 -67 -179 179 -179 -148 128 -177 179 67 -66 -60 -160 -15 -175 56 -89 58 9 1 .69 179 -155 111 180 -175 177 176 60 -79 -49 -180 177 63 -67 -60 -161 -25 -169 177 -102 -63 10 1 .70 -179 -68 -39 -175 -173 175 179 179 -82 -38 -177 -55 175 61 -49 -146 -39 -177 -59 -74 -60 11 1 .71 -175 -71 -17 174 -68 -179 -179 -179 -60 -36 -173 176 63 173 178 -98 147 -176 -52 106 58 12 1 .73 -177 -68 -28 174 -69 -179 -179 59 -133 44 -178 -162 78 -60 -178 -147 -22 -179 -58 105 179 13 1 .80 179 -156 138 177 -170 178 175 59 -90 120 174 178 63 172 -60 -156 165 177 57 -92 60 14 1 .83 -179 -76 96 176 -172 177 -86 -59 -77 -33 -179 -58 173 61 70 -145 145 -179 -58 103 -60 15 1 .84 -179 -76 97 176 -173 176 -86 -59 -77 -33 -179 -58 173 -178 70 -145 146 -179 -58 103 -60 16 1 .87 -179 -75 93 172 -172 178 176 61 -77 -32 177 -57 173 61 70 -158 -28 -171 178 -101 -63 17 1 .89 -178 -80 -28 -177 -66 -178 -179 -59 -153 143 176 -176 69 174 -59 -139 -20 177 -57 -73 -179 18 1 .90 -177 -61 -41 -179 -173 176 -84 61 -109 37 -177 -53 171 60 -52 -148 -1 -173 -58 101 177 19 1 .92 -178 -78 77 178 -67 -178 -179 60 -76 80 179 -175 66 51 -60 -157 -26 -177 178 77 59 20 1 .93 -179 -69 124 180 -173 69 -174 60 -82 75 180 -55 175 -178 -49 -156 -26 -178 -178 -100 59 Table 4. List of torsion angles for formyl-Met-Acc5-Phe-OMe. f ormyl Met Acc5 Phe OM AG e * V CO x1 x2 x3 x4 * V CO * V CO x1 x2 e 1 -.467 -178 -73 -30 180 -68 -179 -179 -60 58 36 180 -158 151 174 177 78 -177 2 -.433 -179 -60 108 180 -174 173 81 177 58 36 180 -156 148 174 177 -101 -58 3 -.299 -179 -60 108 180 -174 67 -179 179 58 36 180 -156 148 175 177 -100 -178 4 -.165 -179 -64 104 180 -71 -73 179 -60 58 36 180 -157 -30 -177 177 -101 59 5 -.140 -179 -66 102 -175 -71 177 82 177 56 39 -177 -157 -30 -177 177 -101 59 6 -.132 -179 -66 102 -175 -71 177 82 177 56 3 9 -177 -157 -29 -178 177 78 -60 7 -.130 -179 -66 102 -175 -71 177 82 177 56 3 9 -177 -157 -30 -177 177 -101 179 8 -.127 -179 -63 108 -176 -174 174 81 176 59 40 170 -138 -26 -179 -62 -62 -60 9 .000 -179 -63 110 -176 -174 67 -178 -59 59 3 9 170 -138 -26 -179 -63 -62 59 10 .374 -179 -67 -38 -180 -173 177 83 57 64 -86 180 -160 -15 178 52 83 60 11 .457 -179 -61 105 180 -72 -74 179 59 58 35 180 -157 146 174 177 -101 -58 12 .4 63 -178 -159 132 -177 -175 171 179 -5 9 55 57 179 -65 138 -174 -62 109 57 13 .466 -178 -65 103 -174 -71 177 82 57 56 38 -177 -158 145 174 176 -100 -178 14 .521 -178 -62 109 -179 -174 68 -179 -60 58 35 177 -70 -33 177 179 -100 -179 15 .629 -178 -62 -33 178 -172 174 179 -60 -51 -40 -177 -83 -35 166 -56 -70 64 16 . 674 -178 -73 -30 -179 -69 -73 179 59 57 37 -177 -159 151 174 177 -101 61 17 .681 -179 -70 126 -176 -169 176 -175 -179 -52 -54 176 -77 122 -168 -58 108 55 18 .694 -178 -76 82 175 -68 -177 179 179 -50 -35 176 -153 -9 177 56 -91 -58 19 .718 0 -69 -33 179 -165 -176 178 -59 59 46 178 -156 151 174 179 79 -178 20 .761 -178 -65 104 -174 -70 -178 -82 -57 59 41 171 -138 -30 179 -62 -61 -59 Tables 1 and 2 give the conformational characteristics of the twenty most stable conformers obtained after the second minimization for each peptide. These conformers are classified by order of increasing relative free energy. For each conformation, we find the relative free energy AG calculated for T = 300 K, and the relative conformational energy AE. The structural characteristics of each conformer are given by indicating the presence or not of intramolecular hydrogen bonds between the different donors and acceptors. The torsion angles for the parent peptide as well as the constrained one are listed in table 3 and table 4, respectively. C. H. Ameziane, M. Lakhder, A. Ezzamarty, Y. Wazady: Comparative conformational study... 62 Acta Chini. Slov. 2002, 49, 55-65. The conformational analysis of the twenty most stable conformers of the parent peptide formyl-Met-Leu-Phe-OMe (table 1) shows that it can adopt varied conformational structures, which can be distributed into four classes: The first class is that of the conformers characterized by the presence of the ß turn structure centered on Met and Leu, and it can be represented by four conformers (conformers 3, 10, 11 and 12). Such a structure is stabilized by an intramolecular hydrogen bond including the CO group of the formyl and NH group of Phe. Figure 4-a gives a stereoscopic superposition view of the four conformers belonging to this group. The second class includes five conformers characterized by the presence ofay turn centered on Met, and stabilized by an intramolecular hydrogen bond involving the CO group of the formyl and NH group of Leu. The stereoscopic superposition view of these five conformers is given in figure 4-b. The third class, which includes five conformers, is characterized by conformations adopting a y turn centered on Leu, and stabilized by an intramolecular hydrogen bond, implying the CO group of Met and NH group of Phe. Figure 4-c gives the stereoscopic superposition of these five conformers. The fourth class gathers structures in a double y turn (a y turn centered on Met and a y turn centered on Leu at the same time), and includes two conformers of formyl-Met-Leu-Phe-OMe. The stereoscopic superposition view of both conformers of this class is presented on the figure 4-d. Figure 4. Stereoscopic superposition view of conformers of different classes obtained in the case of formyl-Met-Leu-Phe-OMe. C. H. Ameziane, M. Lakhder, A. Ezzamarty, Y. Wazady: Comparative conformational study... Acta Chini. Slov. 2002, 49, 55-65. 63 Concerning the constrained tripeptide formyl-Met-Acc5-Phe-OMe, the conformational analysis of the most twenty stable conformers (table 2) shows a great tendency toward the ß turn structure. Indeed, 13 conformers over the 20 most stable conformers, represent this structure. The stereoscopic superposition view of these conformers is given in figure 5. Figure 5. Stereoscopic superposition view of the 13 conformers of formyl-Met-Acc5- Phe-OMe in ß turn structure. Discussion From these results, it appears clear that the parent peptide formyl-Met-Leu-Phe- OMe can adopt several types of structures in such way that we can not favor a precise structure, as compared to other structures. Therefore, it is not easy to extract the conformational characteristics of the chemotactic peptides using only the parent peptide formyl-Met-Leu-Phe-OMe. The conformational analysis results of the geometrically constrained peptides formyl-Met-Acc5-Phe-OMe in which the a,a-disubstituted amino acid Acc5 gives it a certain rigidity, shows the preference of this tripeptide to adopt ß turn conformation. This result is in perfect agreement with the conformational analysis results of the geometrically constrained peptides formyl-Met-Acc6-Phe-OMe that we have carried out with the same method, . Taking into account the findings above and other studies, " we can propose that the active structure of chemotactic peptide is the ß turn structure preferred by the geometrically constrained peptide formyl-Met-Acc5-Phe-OMe. However, in the case of the parent peptide formyl-Met-Leu-Phe-OMe, we can suppose that its activity is due to its flexibility. This flexibility allows the molecule to fit the convenient structure (ß turn) C. H. Ameziane, M. Lakhder, A. Ezzamarty, Y. Wazady: Comparative conformational study... 64 Acta Chini. Slov. 2002, 49, 55-65. during the interaction with the receptor. This result is in perfect agreement with the "Zipper" model of Burgen, . Finally, the comparison of results in table 1 and table 2 enables us to reject the proposal that the formyl group must be free of any intramolecular hydrogen bond in order to be available for the formation of the complex with the receptor. Indeed, among the 20 most stable structures of formyl-Met-Acc5-Phe-OMe, 15 conformers have the formyl group implicated in intramolecular hydrogen bonds, even though this peptide is six times more active than the parent peptide formyl-Met-Leu-Phe-OMe. Conclusion In conclusion, the conformational analysis described in this study and a careful examination of the recent literature enables us to suggest: a) The active structure of chemotactic peptides is the ß turn structure, b) The parent peptide formyl-Met-Leu-Phe-OMe adopts a so flexible structure that can adopt the conformation of the ß turn active structure during the interaction with the receptor, c) A rejection of the importance of the formyl group in the interaction with the receptor. This means that this group is not the pharmacophor contrarily to the result found by a recent study. References and Notes 1. Schiffmann, E.; Corcoran, B. A.; Wahl, S. M. Proc. Nathl. Sci. USA 1975, 72, 1059-1062. 2. Showeil, H. J.; Freer, R. J.; Zigmond, S. H.; Schiffmann, E.; Aswanikumar, S.; Corcoran, B. A.; Becker, E. L. J. Exp. Med. 1976, 143; 1154-1169. 3. Toniolo, C; Bonora, G. M.; Schowell, H. J.; Becker, E. L. Biochemistry 1984, 23, 698-704. 4. Iqbal, M.; Balaram, P.; Showell, H. J.; Freer, R. J.; Becker, E. L. FEBS Letters, 1984,165, 171-174. 5. Bardi, R.; Piazzesi, A. M.; Toniolo, C; Ry, P. A.; Ragothama, S.; Balaram, P. Int. J. Peptide Protein Res. 1986,27,229-238. 6. Lajoie, G.; Sauve, G.; Rao, V. S.; Di Paola, A.; Belleau, B. Int. J. Immunopharmac. 1989, 11, 467-474. 7. Michel, A. G.; Lajoie G.; Ameziane, C. H. Int. J. Peptide Protein Res. 1990, 36, 489-498. 8. Dugas, H.; Laroche, M.; Ptak, M.; Labbé, H. Int. J. Peptide Protein Res. 1993, 41, 595-605. 9. Vertuani, G.; Boggian, M.; Breveglieri, A.; Cavicchioni, G.; Spisani, S.; Scatturin, A. Amino Acids, 1995, 9, 375-383. 10. Cavicchioni, G.; Breveglieri, A.; Boggian, M.; Vertuani, G.; Reali, E.; Spisani, S. J. Pept. Sci. 1996, 2, 135-140. 11. Santini, A.; Barone, V.; Bavoso, A.; Benedetti, E.; Di Biasio, B.; Fraternali, F.; Lelj, F.; Pavone, V.; Pedone, C; Crisma, M.; Bonora, G. M.; Toniolo, C. Int. J. Biol. Macromol., 1988,10, 292-299. 12. Valle, G.; Crisma, M.; Toniolo, C. Can. J. Chem. 1988, 66, 2575-2582. 13. Becker, L.; Bleich, H. E.; Day, A.; Freer, R. J.; Glasel, J. A.; Visintainer, J. Biochemistry 1979, 18, 4656-4668. 14. Morfew, A. J.; Tickle, I. Cryst. Struct. Commun., 1981,10, 781-788. C. H. Ameziane, M. Lakhder, A. Ezzamarty, Y. Wazady: Comparative conformational study... Acta Chini. Slov. 2002, 49, 55-65. 65 15. Bakir, M.; Stevens, E. S. Int. J. Peptide Protein Res. 1982,19, 133-136. 16. Sukumar, M.; Raj, P. A.; Balaram, P.; Becker, E. L. Biochem. Biophys. Res. Commun. 1985, 128, 339-344. 17. Michel, A. G.; Ameziane, C. H.; Bredin, N. Can. J. Chem. 1992, 70, 596-603. 18. Nemethy, G.; Pottle, M. S.; Scheraga, H. A. J. Phys. Chem. 1983, 87, 1883-1887. 19. Momany, F. A.; McGuire, R. F.; Burgess, A. W.; Scheraga, H. A. J. Phys. Chem. 1975, 79, 2361-2381. 20. Zimmerman, S. S.; Pottle, M. S.; Nemethy, G.; Scheraga, H. A. Macromoleculesl977,10, 1-9. 21. Wazady, Y.; Ameziane, C. H.; Lakhdar, M. Ezamarty, A. Int. J. Mol. Sci.2001, 2, 1-9. 22. Toniolo, C; Crisma, M.; Valle, G.; Bonora, G. M.; Polinelli, S.; Becker, E. L.; Freer, R. J.; Rao, R. B.; Balaram, P.; Sukumar, M. Pept. Res., 1989, 2, 275-281. 23. Nogrady, T. Medicinal Chemistry: A biochemical approach; Oxford University Press 1988, pp 47-49. Povzetek Predstavljamo študijo povezave med konformacijo glavne verige in biološko aktivnostjo kemotakticnih peptidov formil-Met-Leu-Phe-OMe in formil-Met-Acc5-Phe-OMe s teoretsko metodo PEPSEA. Dokazali smo, da ima osnovni peptid formil-Met-Leu-Phe-OMe fleksibilno strukturo in da ima konformacijsko oviran peptid tendenco tvorbe ß zavoja. Podan je tudi dokaz proti veljavnosti hipoteze, da je za interakcijo z receptorjem potrebna prisotnost formilne skupine. C. H. Ameziane, M. Lakhder, A. Ezzamarty, Y. Wazady: Comparative conformational study...