Theoretical conformational analysis of peptides. Evolution of a strategy and its application to cholecystokinin analogs

Abstract

. Can. J. Chem. 66,2703Chem. 66, (1988. Scheraga's ECEPP program has been used to determine the relationship between one-point energies and the energies minimized by a quadratic procedure, for different sized (+, +, x ,) dihedral angle grid searches of simple peptides. Based on these trials, a new subroutine, INIT, has been written and incorporated into the program. This subroutine calculates the one-point ECEPP energies of up to 200,000 random permutations of (4, +) = 0, + 90, 180 and (X ,) = -60, 180 with all w = X,] = 180; after each 40,000 permutations, the structures having the 10 lowest energies are ordered and selected for minimization. The ECEPP program has been modified further to provide an MMP2(85) input file as part of its normal output. This allows structures located by INIT to be minimized automatically, and then refined by the Newton-Raphson minimization and MMPEP parameters of MMP2(85).During the development of this protocol, it has been found that MMPEP correctly reproduces the C7 conformational preference of the alanyl dipeptide in nonpolar media, and also the experimentally observed shift to a~ and PII conformations in polar solvents, when the dielectric constant E = 78.5 D. This dielectric constant has, therefore, been selected for a conformational analysis, using INITIMMPEP, of the peptides Gly-Trp-Met-Asp-Phe-NH2 (GLMAP), Gly-D-Trp-Met-Asp-Phe-NH2 (GDMAP), and Gly-Gly-Met-Asp-Phe-NH2 (GGMAP); GLMAP is CCK-5, a cholecystokinin fragment possessing anticonvulsant activity, which is found in the brain. The analogs GDMAP and GGMAP are not active, or much less so than GLMAP. One strongly preferred structure has been found, in each case, for GLMAP (GLMAP3) and GDMAP (GDMAP39). These structures are very similar, in the nature of the edge-to-face stacking of their Trp and Phe aromatic rings, but the C-terminal regions differ. The conformation of the C-terminal tetrapeptide of GLMAP3 is identical to a previously calculated structure of CCK-4. A comparison of the C-terminal regions of GLMAP3 and GDMAP39 with the structure of 5,5-diphenylhydantoin suggests that the mechanisms of anticonvulsant action of phenytoin and CCK-5 are not the same. In the absence of an aromatic-aromatic interaction, no clear-cut conformational preference is found for GGMAP. The structure of GGMAP whose C-terminal region is the same as that of GLMAP3 (GGMAP20) is 1.51 kcal/mol higher in energy than the lowest energy structure, and lacks the hydrophobic wall provided by the Trp residue of GLMAP3. Au cours du dtveloppement de ce protocole, on a trouvt que MMPEP reproduit correctement la preference conformationnelle du C7 du dipeptide de l'alanyle dans des milieux non-polaues ainsi que le dtplacement observt exptrimentalement vers les conformations c i~ et PI1 dans des solvants polaires, lorsque E = 78,5 D. On a donc choisi cette constante ditlectrique pour une analyse conformationnelle, utilisant le programme INITIMMPEP, des peptides Gly-Trp-Met-Asp-Phe-NH2 (GLMAP), Gly-D-Trp-Met-Asp-Phe-NH2 (GDMAP) et Gly-Gly-Met-Asp-Phe-NH2 (...

1992 Lemieux Award Lecture Studies related to the penicillin receptor

“…For small molecules, a rather complete conformational analysis is feasible, using the dihedral driver of M M~, but this strategy is impractical for a peptide. The conceptual breakthrough was made by Stephen Bruder and Kiyull Yang, who devised a random number strategy that screens hundreds of thousands of torsional isomers, using ECEPP, minimizes several hundred low-energy structures of this set, and then automatically converts these to the M M~ format for final minimization of all bond lengths, bond angles, and dihedral angles (56).…”

“…To obtain a model of a penicillin receptor, we selected the sequence around the active site of Streptomyces R61, i.e., Ac-Val-Gly-Ser-Val-Thr-Lys-NHMe, for examination by the Bruder-Yang strategy (56).We assumed that we were seeking a low-energy conformation in which the terminal amino group of lysine is 6-8 A from the serine hydroxyl oxygen. Following a preliminary search of 200 000 structures and examination of 50 low-energy structures we found the conformation shown in Fig.…”

MMPEP: Development and evaluation of peptide parameters for Allinger's MMP2(85) programme, including calculations on crambin and insulin

“…The present article is concerned with the development of MMPEP, an all-atom parameterization of MM2 for peptides. The following article (19) describes modifications to ECEPP, which allow this latter programme to serve as a very convenient starting point for the application of MMPEP to the conformational analysis of peptides. Full details of these programming changes will be provided free of charge to all authorized users of MMP2 (85).…”

“…An STO-3G optimization of propane was used to obtain C-H (type 1-5) bond lengths for the side chains of amino acids such as valine and leucine. Finally, a 3-21G* optimization of 2-mercaptoethanol provided the S-H (type [15][16][17][18][19][20][21][22][23][24][25] bond length of cysteine.…”

“…The question of strategy is examined in the following paper (19). Here we present tests of the parameters, performed on experimental crystal structures of several peptides and proteins.…”