Predicting the limit of intramolecular H-Bonding with classical molecular dynamics

The energetics of intramolecular recognition processes are governed by the balance of pre-organization and flexibility that is often difficult to measure and hard to predict. Here, by using state-of-the-art classical molecular dynamics simulations, we predict and quantify the effective strength of intramolecular interactions between H-bond donor and acceptor sites separated by a variable alkyl linker—in a variety of solvents and including crowded solutions. The fine balance of entropic and enthalpic contributions posits a solvent-dependent limit to the occurrence of intramolecular H-bonding. Nevertheless, H-bond free energies are rigidly shifted among different solvents with, for example, a systematic  13 kJ/mol gap between water and chloroform. Molecular crowding shows little effects on thermodynamic equilibrium but it induces pronounced variations on H-bond kinetics. The results are in quantitative agreement with available experimental measurement (in chloroform) and showcase a general strategy to interrogate molecular interactions in different environments, extending the limits of current experiments towards the prospective prediction of H-bond interactions in pharmaceutical, agrochemical, and technological contexts.