Conformational choices for the stereochemically constrained γ-amino acid residue gabapentin: theoretical studies and correlation with experimental results

Gabapentin (1-aminomethylcyclohexaneacetic acid, Gpn) is an achiral, conformationally constrained γ amino acid residue. A survey of available crystal structures of Gpn peptides reveals that the torsion angles about the Cγ—Cβ(θ1) and Cβ—Cα(θ2) bonds are overwhelmingly limited to gauche,gauche (g+g+/g−g−) conformations. The Gpn residue forms C7 and C9 hydrogen bonds in which the donor and acceptor atoms come from the flanking peptide units. In combination with α amino acid residues αγand γαsegments can adopt C12 hydrogen bonded structures. The conformational choices available to the Gpn residue have been probed using energy calculations, adopting a grid search strategy. Ramachandran Φ-ψ maps have been constructed for fixed values of θ1 and θ2, corresponding to the gauche and trans conformations. The sterically allowed and energetically favorable regions of conformational space have been defined and experimental observations compared. C7 and C9 hydrogen bonded conformational families have been identified using a grid search approach in which θ1 and θ2 values are varied over a range of ±10° about ideal values at 1° intervals. The theoretical analysis together with experimental observations for 59 Gpn residues from 35 crystal structures permits definition of the limited range of conformational possibilities at this γ amino acid residue