In nature, proline residues carry several post-translational modifications (PTMs), including 4R hydroxylation and glycosylation. A recent study synthesized contiguously hydroxylated and glycosylated nonaproline peptides and revealed that both PTMs lead to a significant increase in the thermal stability of PPII relative to the unmodified oligoproline. The increased stability of the hydroxylated peptide can be explained by increased stability of the trans isomer due to stereoelectronic effects. However, the effects of glycosylation cannot be completely explained by stereoelectronics since previous experimental results indicate that 4R-glycosylation does not produce observable changes in the trans preference compared to 4R-hydroxylation. We therefore used sophisticated molecular modeling techniques to determine the reason for the further increase in thermal stability upon glycosylation. Free energy estimates obtained from adaptively biased molecular dynamics calculations in implicit (explicit) solvent are -9 kcal mol(-1) (-20 kcal mol(-1)) for the hydroxylated compound and -9 kcal mol(-1) (-46 kcal mol(-1)) for the glycosylated compound indicating that direct solvent-peptide interactions are vital for explaining the glycosylation effects on PPII stability. Our data reveals for the first time that interactions between the hydroxyl groups in the glycosylated compound and water act in a complementary fashion with stereoelectronic effects to stabilize the in these substituted oligoproline peptides.