Enthalpic and entropic contributions to the activation free energy of single noncovalent bonds in molecular systems: A computational methodology

Insight into enthalpic and entropic contributions to the activation free energy of noncovalent bonds is crucial for understanding various phenomena in molecular systems, from formation of different molecular conformers to complex biophysical and biochemical processes. Standard experimental and computational methods provide only the average strength of noncovalent bonds. In this paper, we present a simple, formal, computational framework to determine both energy contributions for a single bond. Our approach is based on steered molecular dynamics simulations, the dynamic force spectroscopy method, and a modified theoretical model of force -induced bond rupture. To demonstrate the methodology, the enthalpic and entropic components for a single intramolecular hydrogen bond of a peptide helix were determined. The sum of the contributions is in agreement with the previously reported Gibbs energy for intramolecular hydrogen bonds. The proposed methodological framework is universal and can be applied to other noncovalent interactions in various molecular systems.