Development of a molecular dynamics based method for alchemical free energy calculation

Abstract

Free energies at different conditions are essential to obtain thermodynamic properties of industrial and academic interest, such as those related to protein-ligand binding and solute-solvent interactions. Molecular Dynamics (MD) simulations have been widely applied in these calculations, often associated with alchemical transformations, which involve non-physical thermodynamic pathways. Among the alchemical approaches, soft-core modeling is the most common in recent studies, being implemented in many of the main MD software packages. However, a promising technique called Linear Basis Function (LBF) was suggested recently. This model overcomes a major drawback of the scaling method, from which it derives, and maintains its advantages to create a more flexible methodology compared to the soft-core approach. In the present work, we propose a variation of the LBF method to reduce the number of required parameters while formulating efficient alchemical protocols. We performed solvation free energy calculations and obtained octanol-water partition coefficients of organic molecules to validate our proposal. Partition coefficients are excellent properties for testing the efficiency of free energy methods due to the large amount of experimental and simulated data available in the literature. Results obtained from three distinct protocols based on different optimization schemes are presented. Comparisons with the soft-core method and with literature data show the effectiveness of our strategy. Therefore, this work reinforces the benefits of the LBF approach and provides simplified models potentially applicable to various other systems.