Identifying Free Energy Hot-Spots in Molecular Transformations

Area of Science:

• Computational chemistry
• Molecular modeling
• Thermodynamics

Background:

• Free energy is crucial in materials and natural sciences, particularly in drug design and catalyst optimization.
• Current computational methods struggle to provide detailed insights into calculated free energy and underlying chemical/physical processes.
• Understanding vibrational free energy contributions is key to advancing molecular simulations.

Purpose of the Study:

• To develop a generally applicable method for dissecting vibrational free energy into atomic or group contributions.
• To provide deeper insights into computational free energy calculations.
• To bridge the gap between computational predictions and experimental observations.

Main Methods:

• A novel spectrum-based ansatz is presented to identify contributions to vibrational free energy.
• The method is applied to analyze bromodomain-inhibitor binding.
• The anomeric effect in glucose is studied, including simulation and experimental infrared spectroscopy.

Main Results:

• The spectrum-based method successfully identifies atomic/group contributions to vibrational free energy.
• Quantitative evidence supporting chemical intuition was obtained for bromodomain-inhibitor binding.
• Excellent agreement was found between simulated and experimental infrared spectra for glucose.

Conclusions:

• The developed ansatz offers a powerful tool for analyzing vibrational free energy in computational studies.
• This method enhances the interpretability of free energy calculations in diverse chemical systems.
• The findings facilitate a more profound understanding of molecular interactions and chemical phenomena.