Correction Schemes for Absolute Binding Free Energies Involving Lipid Bilayers br

Absolute binding free-energy (ABFE) calculations areplaying an increasing role in drug design, especially as they can beperformed on a range of disparate compounds and direct comparisonsbetween them can be made. It is, however, especially important to ensurethat they are as accurate as possible, as unlike relative binding free-energy(RBFE) calculations, one does not benefit as much from a cancellation oferrors during the calculations. In most modern implementations of ABFEcalculations, a particle mesh Ewald scheme is typically used to treat theelectrostatic contribution to the free energy. A central requirement of suchschemes is that the box preserves neutrality throughout the calculation.There are many ways to deal with this problem that have been discussedover the years ranging from a neutralizing plasma with a post hoccorrection term through to a simple co-alchemical ion within the samebox. The post hoc correction approach is the most widespread. However, the vast majority of these studies have been applied to asoluble protein in a homogeneous solvent (water or salt solution). In this work, we explore which of the more common approacheswould be the most suitable for a simulation box with a lipid bilayer within it. We further develop the idea of the so-called Rocklincorrection for lipid-bilayer systems and show how such a correction could work. However, we also show that it will be difficult tomake this generalizable in a practical way and thus we conclude that the use of a"co-alchemical ion"is the most useful approach forsimulations involving lipid membrane systems.