Solubility prediction of organic molecules with molecular dynamics simulations

TL;DR

This paper introduces a molecular dynamics simulation approach using well-tempered Metadynamics to accurately predict the solubility of organic molecules by calculating free energy differences at crystal kink sites, aligning well with experimental data.

Contribution

The study develops a novel simulation method combining constant chemical potential MD and Metadynamics to compute solubility based on free energy differences at kink sites.

Findings

Successfully reproduces experimental solubility trends for urea and naphthalene.

Demonstrates the method's effectiveness across various solvents.

Provides a detailed free energy-based framework for solubility prediction.

Abstract

We present a molecular dynamics simulation method for the computation of the solubility of organic crystals in solution. The solubility is calculated based on the equilibrium free energy difference between the solvated solute and its crystallized state at the crystal surface kink site. In order to efficiently sample the growth and dissolution process, we have carried out well-tempered Metadynamics simulations with a collective variable that captures the slow degrees of freedom, namely the solute diffusion to and adsorption at the kink site together with the desolvation of the kink site. Simulations were performed at different solution concentrations using constant chemical potential molecular dynamics and the solubility was identified at the concentration at which the free energy values between the grown and dissolved kink states were equal. The effectiveness of this method is demonstrated by its success in reproducing the experimental trends of solubility of urea and naphthalene in a variety of solvents.