Structural versatility of peptides from C^α,α‐dialkylated glycines. I. A conformational energy computation and x‐ray diffraction study of homo‐peptides from C^α,α‐diethylglycine

Abstract

Conformational energy computations on a derivative and a homo‐dipeptide of Cα,α‐diethylglycine were performed. In both cases the N‐ and C‐terminal groups are blocked as acetamido and methylamido moieties, respectively. It was found that the Cα,α‐diethylglycine residues are conformationally restricted and that the minimum energy conformation corresponds to the fully extended C5 structure when the NCαC′ bond angle is smaller than 108° (as experimentally observed). The results of the theoretical analysis are in agreement with the crystal‐state structural propensity of the complete series of N‐trifluoroacetylated homo‐peptides of this Cα,α‐dialkylated residue from monomer to pentamer, determined by x‐ray diffraction and also described in this work. Interestingly, for the first time, a crystallographically planar peptide backbone was observed (in the protected tripeptide). A comparison with peptides of Cα,α‐dimethylglycine, Cα‐methyl, Cα‐ethylglycine, and Cα,α‐di‐n‐propylglycine indicates that the fully extended conformation becomes more stable than the helical structures when both amino acid side‐chain Cβ atoms are substituted.

Design and Synthesis of Chiral .ALPHA.,.ALPHA.-Disubstituted Amino Acids and Conformational Study of Their Oligopeptides

“…4). [12][13][14] The extended C 5 -conformation is an extended planar conformation of the peptide-backbone, showing two torsion angles of fϭ180°, jϭ180°. Achiral homopeptides composed of dipropylglycine, dibutylglycine, or diphenylglycine also preferentially form the extended conformation.…”

Linear oligopeptides. 188.Crystallographic characterization of the conformation of the 1-aminocyclopentane-1-carboxylic acid residue in simple derivatives

“…"-dialkylated residues with linear substituents, like Ca~a-dimethylglycine or a-aminoisobutyric acid (Aib) (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16), Capa-diethylglycine (Deg) (5,10,17), and Ca9-di-n-propylglycine (Dpg) (5,10,18), relatively few studies have been reported on peptides containing l-aminocycloalkane-I-carboxylic acids (Accn, where n is the number of carbon atoms in the cycloalkane ring). Recent X-ray diffraction investigations in our laboratory suggest that both l-aminocyclohexane-1-carboxylic acid (Acc6) (19)(20)(21)(22) and l-aminocyclopentane-I-carboxylic acid (Acc5), earlier referred to as cycloleucine and abbreviated as Cle, Cyl, cycloLeu or cLeu (23) strongly prefer folded backbone conformations in the 310/ahelical region of the conformational space (@ = k 6 0 f 20°, $ = k 30" 2 20") (24).…”

Factors governing helical preference of peptides containing multiple alpha,alpha-dialkyl amino acids.

“…While the two major allowed conformational areas were associated with either right-or left-handed helical conformations (both a and 310), the calculation also revealed other sets of energetically feasible values for 4 and q, adjacent to the a,a-dialkyl residue associated with extended structures as well as turns. The effect on conformation of alkyl groups larger than methyl as substituents in a,a-dialkyl amino acids has also been investigated (11,12). Despite the variety of conformations theoretically available to a,a-dialkyl amino acids, the impact of multiple substitutions ofthis type of amino acid on the overall conformation of a peptide is dramatic.…”