  Alchemical free energy calculations via molecular dynamics have been widely
used to obtain thermodynamic properties related to protein-ligand binding and
solute-solvent interactions. Although soft-core modeling is the most common
approach, the linear basis function (LBF) methodology [Naden, L. N.; et al. J.
Chem. Theory Comput. 2014, 10 (3), 1128; 2015, 11 (6), 2536] has emerged as a
suitable alternative. It overcomes the end-point singularity of the scaling
method while maintaining essential advantages such as ease of implementation
and high flexibility for postprocessing analysis. In the present work, we
propose a simple LBF variant and formulate an efficient protocol for evaluating
van der Waals and Coulomb components of an alchemical transformation in tandem,
in contrast to the prevalent sequential evaluation mode. To validate our
proposal, which results from a careful optimization study, we performed
solvation free energy calculations and obtained octanol-water partition
coefficients of small organic molecules. Comparisons with results obtained via
the sequential mode using either another LBF approach or the soft-core model
attest to the effectiveness and correctness of our method. In addition, we show
that a reaction field model with an infinite dielectric constant can provide
very accurate hydration free energies when used instead of a lattice-sum method
to model solute-solvent electrostatics.
