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Conformational energy studies on N‐methylated analogs of thyrotropin releasing hormone, enkephalin, and luteinizing hormone‐releasing hormone
Author(s) -
Manavalan Parthasarathy,
Momany Frank A.
Publication year - 1980
Publication title -
biopolymers
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.556
H-Index - 125
eISSN - 1097-0282
pISSN - 0006-3525
DOI - 10.1002/bip.1980.360191103
Subject(s) - conformational isomerism , chemistry , dipeptide , peptide bond , thyrotropin releasing hormone , stereochemistry , residue (chemistry) , peptide , hydrogen bond , hormone , molecule , biochemistry , organic chemistry
Empirical conformational energy calculations have been carried out for N‐methyl derivatives of alanine and phenylalanine dipeptide models and N‐methyl‐substituted active analogs of three biologically active peptides, namely thyrotropin‐releasing hormone (TRH), enkephalin (ENK), and luteinizing hormone‐releasing hormone (LHRH). The isoenergetic contour maps and the local dipeptide minima obtained, when the peptide bond (ω) preceding the N‐methylated residue is in the trans configuration show that (1) N‐methylation constricts the conformational freedom of both the i th and ( i + 1)th residues; (2), the lowest energy position for both residues occurs around ϕ = −135° ± 5° and ψ = 75° ± 5°, and (3) the α L conformational state is the second lowest energy state for the ( i + 1)th residue, whereas for the i th residue the C 5 (extended) conformation is second lowest in energy. When the peptide bond (ω i ) is in the cis configuration the i th residue is energetically forbidden in the range ϕ = 0° to 180° and ψ = −180° to +180°. Conformations of low energy for ω i = 0° are found to be similar to those obtained for the trans peptide bond. In all the model systems (irrespective of cis or trans ), the α R conformational state is energetically very high. Significant deviations from planarity are found for the peptide bond when the amide hydrogen is replaced by a methyl group. Two low‐energy conformers are found for [(N‐Me)His 2 ]TRH. These conformers differ only in the ϕ and ψ values at the (N‐Me)His 2 residue. Among the different low‐energy conformers found for each of the ENK analogs [ D ‐Ala 2 ,(N‐Me)Phe 4 , Met 5 ]ENK amide and [ D ‐Ala 2 ,(N‐Me)Met 5 ]ENK amide, one low‐energy conformer was found to be common for both analogs with respect to the side‐chain orientations. The stability of the low‐energy structures is discussed in the light of the activity of other analogs. Two low‐energy conformers were found for [(N‐Me)Leu 7 ]LHRH. These conformations differ in the types of bend around the positions 6 and 7 of LHRH. One bend type is eliminated when the active analog [ D ‐Ala 6 ,(M‐Me)Leu 7 ]LHRH is considered.