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.

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