Low-energy conformational domains of polypeptides, characterized by a random-search and minimization procedure

Abstract

This paper is declicntecl t o Professor Sigeru Huzinaga on the occnsion ($his 65th birthdclyANDRE G. MICHEL, CHAKIB AMELIANE-HASSANI, and NATHALIE BREDIN. Can. J. Chenl. 70, 596 (1992). In the framework of molecular mechanics conformational energy calculations, a random-search and minimization procedure is presented to characterize low-energy domains of polypeptidic structures. Rather than striving for global minima, populations of conformers are randomly generated, and their energy is minimized in order to study their intrinsic properties. The application to the opioid peptide Met-Enkephalin allowed the identification of low-energy domains that are compared with previous results of conformational studies on this molecule. Our method gives a complete overview of the conformational behaviour of the polypeptide under study, including previously reported structures as determined from experimental and theoretical studies. To illustrate the usefulness of this method to determine bioactive peptidic structures and their active conformers, the application to geometrically constrained chemotactic tripeptides is presented.Key words: peptides, conformation, theoretical prediction.ANDRT. G. MICHEL, CHAKIB AMEZIANE-HASSANI et NATHALIE BREDIN. Can. J. Chem. 70, 596 (1992). Une mCthode thCorique de caractCrisation des domaines conformationnels des molCcules polypeptidiques est presentee. Les calculs d'Cnergie conformationnelle sont effectuCs dans le cadre empirique de la mCcanique molCculaire. PlutBt que chercher B localiser le minimum global d'une hypersurface CnergCtique, des populations de conform6res sont gCnCrees en vue d'en Ctudier les propriCtCs intrinskques. L'application au peptide opiact Met-Enktphaline a permis d'identifier des domaines dans la population gCnerCe et de comparer ces rCsultats des Ctudes conformationnelles antkrieures. On dCmontre que cette approche fournit une vue complkte du comportement conformationnel du polypeptide, incluant les structures proposkes par des travaux thCoriques ou expCrimentaux. Afin d'illustrer I'applicabilitC de la mCthode pour I'identification de conformation d'intCr&t biologique, une Ctude a kt6 menCe sur des tripeptides chimiotactiques a gCometrie restreinte.

Conformational Study of Met-Enkephalin Based on the ECEPP Force Fields

“…The internal coordinates of the lowest energy ECEPP/2 structure listed in Montcalm et al (32) (which were obtained from (15) and further used for comparison with those determined from the AMBER and CHARMM force fields) are very close to those listed in Table 3. The internal coordinates in that reference suggested a Gly 3 -Phe 4 Type-II9 b-turn, rather than a Gly 3 -Phe 4 Type-IV b-turn obtained here based on Table 2.…”

“…The lowest energies of Met-enkephalin without explicit solvation effects were previously determined based on the ECEPP/2 potential (6,(10)(11)(12)14,15) and the ECEPP/3 potential (11,13). Local energy minima not much higher than global minima were sampled and classified by Freyberg and Braun (10) based on the ECEPP/2 potential, and by Eisenmenger and Hansmann (11) based on both ECEPP/2 and ECEPP/3 potentials (with the peptide dihedral angles v fixed at 180°).…”

Structural Requirements for Molecular Recognition by fMLP Analogs Receptors: Comparative Conformational Analysis of (for-Met-Leu-Phe-OMe) and its Thioamide Analog (for-Met-Leuψ[CSNH]Phe-OMe)

“…The method used in this study is called PEPSEA (PEPtidic SEArch). It was developed by Michel et al in the structural chemistry laboratory of the Sherbrooke University, 26 and it has shown its effectiveness in the theoretical Ameziane et al: Structural Requirements for Molecular Recognition ... stable conformers. For each two considered tripeptides, 20.000 conformers were randomly generated and energy minimized to the closest minima.…”

“…conformational studies of several peptide molecules and their structure-activity relationship. 16,[24][25][26][27][28][29][30][31][32] 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.…”

Theoretical Conformational Analysis of Chemotactic Peptides Formyl-Met-Leu-Phe-OMe and Formyl-Met-Acc6-Phe-OMe

“…It was developed in the structural chemistry laboratory of the Sherbrooke University [14]. 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.…”