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

Abstract

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 C^γ—C^β(θ₁) and C^β—C^α(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.