Intramolecular hydrogen bond-controlled prolyl amide isomerization in glucosyl 3(S)-hydroxy-5-hydroxymethylproline...

Area of Science:

• Computational chemistry
• Molecular modeling
• Organic chemistry

Background:

• Peptide bond isomerization is critical in protein folding and function.
• Proline-containing peptides exhibit unique conformational preferences due to cis/trans isomerization.
• Understanding factors influencing proline amide bond conformation is essential for drug design.

Purpose of the Study:

• To computationally investigate the conformational preferences of novel spirocyclic proline-based peptide mimics.
• To explore the role of stereochemistry at the C-5 position of proline in modulating amide bond isomerization.
• To develop and validate a computational protocol for conformational analysis of complex proline hybrids.

Main Methods:

• A combined computational approach using molecular mechanics (MM) and density functional theory (DFT) was employed.
• Systematic and Monte Carlo searches were used to explore the conformational space.
• Gas-phase and continuum solvation (PCM) models were utilized to simulate different environments.

Main Results:

• Both investigated compounds showed a preference for the cis conformation in the gas phase.
• Inclusion of water (PCM) reduced the cis population, aligning with experimental data.
• Intramolecular hydrogen bonding involving the C-5 hydroxymethyl group significantly influenced cis/trans isomerization thermodynamics.

Conclusions:

• The stereochemistry of the C-5 hydroxymethyl substituent in proline mimics plays a critical role in controlling cis/trans prolyl amide isomerization.
• Hydrogen-bonding interactions are key to tuning the conformational equilibrium.
• Strategic placement of substituents allows for the design of peptide mimics with high cis prolyl amide conformer populations.