Factors governing the conformational tendencies of C-alpha-ethylated alpha-amino acids: chirality and side-chain size effects

The intrinsic conformational properties of the N-acetyl-N'-methylamide derivatives of D-C-alpha-ethylglycine (Abu), D-C-alpha-methyl-C-alpha-ethylglycine (Iva), and C-alpha,alpha- diethylglycine (Deg) have been investigated using quantum mechanical calculations in the gas phase and in chloroform, dichloromethane and aqueous solutions. Although the large number of flexible dihedral angles results in many minimum energy conformations, only a few of them are energetically representative because of the repulsive interactions between the ethyl groups and the backbone atoms. The conformational restrictions imposed by such repulsions increase as follows: Abu < Iva < Deg. The most important characteristics of the investigated residues are as follows: (i) the conformation tendencies of Abu resemble those of standard residues with similar constitution (e.g., Val or Leu); (ii) the properties of Iva are relatively similar to those of C-alpha,alpha-dimethylglycine, which is the simplest C-alpha,alpha-dialkylated alpha-amino acid, even though the former is more restricted than the latter; (iii) the conformational flexibility of Deg is even lower than that of C-alpha,alpha-dialkylated residues with bulkier side groups (e.g., C-alpha,alpha-diphenylglycine and C-alpha,alpha-dibenzylglycine).