Frank A. Momany

Conformational analysis of Methionine-Enkephalin and some analogs

Abstract Conformational energy calculations on Methionine-Enkephalin and on several of its analogues indicate that the calculated lowest energy conformation of the native enkephalin may not be the conformer which interacts at the opioid active site. Substitution at the end groups and various D and L-Alanine analogs were examined and a low energy conformation which differs from the native low energy conformer was found for the very active analog, [D-Ala2]-Met-Enkephalin-NH2. The stereopositions of side-chain functional groups are discussed and compared to the structure of morphine.

Local geometry maps and conformational transitions between low-energy conformers of N-acetyl-N′-methyl glycine amide: An ab initio study at the 4–21g level with gradient relaxed geometries

Abstract Energy pathways between the α R , β′, C 7 eq and β-regions of the conformational energy surface of N -acetyl N ′-methyl glycine amide were obtained by SCF ab initio calculations on the 4–21G level with gradient geometry optimization at each point. The calculations point to the possibility that no barrier exists at this computational level between α R and β′. The variation of geometry (bond distances and bond angles) with conformation is analyzed in detail and the geometrical parameters which should be treated as variables in both empirical energy calculations and, possibly, in the fitting of polypeptide chains in proteins by X-ray methods, are identified. The study shows that, in general, Local Geometry Maps (of conformationally dependent structural trends) are as important as Local Energy Maps for the characterization of peptide systems.

On the conformation of Luteinizing Hormone-Releasing Hormone, nuclear Overhauser observation

Abstract Observations of proton nuclear Overhauser effects in the molecule Luteinizing Hormone-Releasing Hormone indicate that a high population of a particular set of conformers exists in water solution. The results can be interpreted as two distinct conformers in which the pGlu 1 ring is in close proximity to aromatic residues further along the sequence of the linear structure. The observed nuclear Overhauser effects were in agreement with the enhancements calculated from models obtained by conformational energy calculations.

Conformational studies on the enkephalin releasing peptides, Tyr-Arg and Tyr-D-Arg

Abstract Conformational energy calculations were carried out on the enkephalin releasing peptides, Tyr-Arg and Try-D-Arg. The conformations of low energy were found to result in two configurations in which the side-chains were either on opposite sides of the backbone (R1) or parallel to one another (R2). A comparison of the two molecules suggests that configuration R2 is most probably the active structure. A method for testing this hypothesis is presented.

Conformational energy studies of the growth hormone inhibitor, cyclo (Aha-Cys-Phe-D-Trp-Lys-Thr-Cys)

Abstract The conformation of the molecule cyclo (Aha- Cys-Phe-D-Trp-Lys-Thr-Cys ) was studied by empirical conformational energy calculations. The low-energy structure found contains a type II bend centered at the D-Trp-Lys residues. The lowest energy conformer has the aromatic ring of DTrp positioned such that the γ-protons of the Lys side-chain are in the shielding region (i.e., perpendicular to the center of the aromatic ring). This is in agreement with the NMR results. A mechanism of action for the inhibition of GH release is presented which suggests a conformational change occurs in the D-Trp side-chain ring upon binding to the receptor. The resulting structure has the Phe-D-Trp ring-ring stacking suggested to be responsible for binding and agonist activity of model growth-hormone releasing peptides.