Entropy and enthalpy calculations from perturbation and integration thermodynamics methods using molecular dynamics simulations: applications to the calculation of hydration and association thermodynamic properties

Calculation of association thermodynamic properties using molecular simulation is essential in computational chemistry. In the case of good agreement with the experimental thermodynamic binding properties, this type of calculation may complement experimental works by providing a microscopic view of the association process. Whereas the calculation of the free energy of association is nowadays well controlled, the calculation of the enthalpy and entropy of association remains difficult in most cases, especially as the association involves hosts and guests of biological interest. A novel method for calculating the entropy change from a molecular dynamics simulation is described. Within the theoretical framework, we discuss the different approximations leading to the final stage of the operational expressions of ΔG and ΔH in the NpT ensemble and we establish an expression for ΔS using the Free Energy Perturbation (FEP) formalism in this statistical ensemble. Finally, we illustrate the theoretical considerations by calculations of the hydration entropy changes between cations of different masses and charges. We extend the study by calculating the changes in the thermodynamic properties of association of inorganic cations with a macrocycle of biological interest.