Peptide mimics containing spirocyclic glucosyl-(3(S)-hydroxy-5(S)-hydroxymethyl)proline (1) and glucosyl-(3(S)-hydroxy-5(R)-hydroxymethyl)proline (2) hybrids differing in the stereochemistry of the polar hydroxymethyl substitutent at the C-5- or (C-delta)-position have been investigated computationally. A computational "build and search" protocol of molecular mechanics systematic search/Monte Carlo search, followed by density functional theory (DFT), has been developed to ensure complete coverage of the large conformational space. Gas-phase DFT optimizations at the B3LYP level of theory lead to a strong preference for the cis conformation in the prolyl amide bond for both compounds 1 and 2. However, inclusion of the solvent water by means of continuum solvation (PCM) results in a reduction of the prolyl amide cis population in both compounds, leading to good agreement with previous experimental observations. Intramolecular hydrogen bonding involving the C-5-hydroxymethyl substitutent is seen to play a crucial role to tune the thermodynamics of prolyl amide cis/trans isomerization and is responsible for the high cis prolyl amide population in compound 2. Our results indicate that H-bond-forming substituents like the hydroxymethyl group at the C-5-position in proline can be used to control cis/trans prolyl amide isomerization. High cis prolyl amide conformer populations can be achieved by proper choice of the stereochemistry at the C-5-position.