Predicting the Limit of Intramolecular Hydrogen Bonding with Classical Molecular Dynamics

Area of Science:

• Chemical Physics
• Computational Chemistry
• Molecular Biophysics

Background:

• Intramolecular recognition is key to molecular function, governed by pre-organization and flexibility.
• Quantifying hydrogen bond energetics in different environments is challenging experimentally.

Purpose of the Study:

• To predict and quantify intramolecular hydrogen bond strength using molecular dynamics (MD) simulations.
• To investigate the influence of solvent and molecular crowding on hydrogen bond energetics and kinetics.

Main Methods:

• Classical molecular dynamics (MD) simulations were employed.
• Analysis focused on donor-acceptor sites linked by variable alkyl chains.
• Energetic contributions (entropic and enthalpic) were calculated across various solvents and crowded solutions.

Main Results:

• Solvent type significantly impacts intramolecular hydrogen bond occurrence due to entropic and enthalpic balances.
• A consistent free energy offset was observed across solvents (e.g., 13 kJ/mol difference between water and chloroform).
• Molecular crowding minimally affected thermodynamic equilibrium but altered hydrogen bond kinetics.

Conclusions:

• MD simulations provide a quantitative strategy for predicting hydrogen bond interactions in diverse environments.
• The findings align with experimental data, validating the simulation approach.
• This method extends experimental capabilities for studying molecular interactions.