Abstract
Hydration free energy calculations in explicit solvent have become an integral part of binding free energy calculations and a valuable test of force fields. Most of these simulations follow the conventional norm of keeping edge length of the periodic solvent box larger than twice the Lennard-Jones (LJ) cutoff distance, with the rationale that this should be sufficient to keep the interactions between copies of the solute to a minimum. However, for charged solutes, hydration free energies can exhibit substantial box size-dependence even at typical box sizes. Here, we examine whether similar size-dependence affects hydration of neutral molecules. Thus, we focused on two strongly polar molecules with large dipole moments, where any size-dependence should be most pronounced, and determined how their hydration free energies vary as a function of simulation box size. In addition to testing a variety of simulation box sizes, we also tested two LJ cut-off distances, 0.65 and 1.0nm. We show from these simulations that the calculated hydration free energy is independent of the box-size as well as the LJ cut-off distance, suggesting that typical hydration free energy calculations of neutral compounds indeed need not be particularly concerned with finite-size effects as long as standard good practices are followed.
Highlights
Solvation free energy calculations based on classical molecular simulations are of considerable interest to test force fields, help guide pharmaceutical drug discovery, and compute other physical properties of interest
We conducted free energy calculations using two different Lennard-Jones cut off distances and, as shown in Figure 2, we find that the hydration free energy is indepen
Motivated by recent work which found profound finitesize effects in calculations of hydration and binding free energies of ionic solutes or ligands, we looked for similar effects on hydration of neutral solutes
Summary
Solvation free energy calculations based on classical molecular simulations are of considerable interest to test force fields, help guide pharmaceutical drug discovery, and compute other physical properties of interest. A large number of tests have focused on computing hydration free energies of both ions [6, 3] and neutral molecules [7]. Most commonly, these calculations are done via a thermodynamic transformation approach. These calculations are done via a thermodynamic transformation approach In this so-called alchemical approach, a solute is taken from the state in which it interacts fully with solvent, to a noninteracting state, via a series of nonphysical intermediate states [11]. We know that alchemical calculations of solvation of ions are affected in subtle ways by several algorithmic issues which profoundly impact the computed free energies, requiring analytical or semi-analytical corrections [6, 3].
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