Regularized Bennett and Zwanzig free energy estimators.

We consider the problem of free energy estimation from the general perspective of regularization and Bayes estimation theory. We try to take advantage of an assumed a priori knowledge of the free energy. We reformulate the original Bennett acceptance ratio method, in this perspective, devise a numerical algorithm to solve it, and give a closed formula to estimate the confidence in the prior. Finally, we test the derived estimators by applying them to a toy model.

Optimal Transport for Free Energy Estimation.

Optimal transport theory is a growing field of mathematics, which has recently found many applications. Here we take advantage of optimal transport for computational free energy estimation. We show analytically, and then via simulation, that this approach is effective in terms of optimizing the barriers of an alchemical transformation.

Solubility Advantage of Amorphous Ketoprofen. Thermodynamic and Kinetic Aspects by Molecular Dynamics and Free Energy Approaches.

Thermodynamic and kinetic aspects of crystalline (c-KTP) and amorphous (a-KTP) ketoprofen dissolution in water have been investigated by molecular dynamics simulation focusing on free energy properties. Absolute free energies of all relevant species and phases have been determined by thermodynamic integration on a novel path, first connecting the harmonic to the anharmonic system Hamiltonian at low T and then extending the result to the temperature of interest. The free energy required to transfer one ketoprofen molecule from the crystal to the solution is in fair agreement with the experimental value. The absolute free energy of the amorphous form is 19.58 kJ/mol higher than for the crystal, greatly enhancing the ketoprofen concentration in water, although as a metastable species in supersaturated solution. The kinetics of the dissolution process has been analyzed by computing the free energy profile along a reaction coordinate bringing one ketoprofen molecule from the crystal or amorphous phase to the solvated state. This computation confirms that, compared to the crystal form, the dissolution rate is nearly 7 orders of magnitude faster for the amorphous form, providing one further advantage to the latter in terms of bioavailability. The problem of drug solubility, of great practical importance, is used here as a test bed for a refined method to compute absolute free energies, which could be of great interest in biophysics and drug discovery in particular.