Effect of Differential Backbone Di-substitution of Gamma Amino Acid Residues on the Conformation and Assembly of their Fmoc Derivatives in Solid and Solution States

Abstract

We studied the effect of variable backbone dimethyl-substitution of γ amino acid residues (γ^2,2 , γ^3,3 and γ^4,4 ) on the conformation and assembly, in crystals and solution of their Fmoc derivatives. The crystal structure of γ^2,2 and γ^4,4 derivatives showed distinct conformations (open/close for γ^2,2 /γ^4,4 ) that differed in torsion angles, hydrogen-bonding and most importantly the π-π Fmoc-stacking interactions (relatively favourable for γ^4,4 -close). Fmoc derivatives existed in an equilibrium between major-monomeric (low energy, non-hydrogen bonded) and minor-dimeric (high energy, hydrogen bonded) populations in solution. The rate of major/minor population exchange was dependent on the position of substitution, highest being for γ^4,4 derivative. In solution, assembly of Fmoc derivatives was solvent dependent, but it was independent of the position of geminal substitution. Crystallization was primarily governed by the stabilization of high-energy dimer by favourable π-π stacking involving Fmoc moieties. High free-energy of the dimers (γ^2,2 -close, γ^3,3 -open/close) offset favourable stacking interactions and hindered crystallization.

Keywords: Fmoc-γx,x-OH; backbone di-substitution; crystal conformation; self-assembly; solution conformation.