Accelerating potential of mean force calculations for lipid membrane permeation: System size, reaction coordinate, solute-solute distance, and cutoffs

Molecular dynamics simulations are capable of predicting the permeability of lipid membranes for drug-like solutes, but the calculations have remained prohibitively expensive for high-throughput studies. Here, we analyze simple measures for accelerating potential of mean force (PMF) calculations of membrane permeation, namely, (i) using smaller simulation systems, (ii) simulating multiple solutes per system, and (iii) using shorter cutoffs for the Lennard-Jones interactions. We find that PMFs for membrane permeation are remarkably robust against alterations of such parameters, suggesting that accurate PMF calculations are possible at strongly reduced computational cost. In addition, we evaluated the influence of the definition of the membrane center of mass (COM), used to define the transmembrane reaction coordinate. Membrane-COM definitions based on all lipid atoms lead to artifacts due to undulations and, consequently, to PMFs dependent on membrane size. In contrast, COM definitions based on a cylinder around the solute lead to size-independent PMFs, down to systems of only 16 lipids per monolayer. In summary, compared to popular setups that simulate a single solute in a membrane of 128 lipids with a Lennard-Jones cutoff of 1.2 nm, the measures applied here yield a speedup in sampling by factor of ∼40, without reducing the accuracy of the calculated PMF.