In drug discovery projects, understanding and controlling the process of permeation of a drug through the cell membrane is almost as important as improving its affinity towards the target. The speed of permeation through a membrane is measured by the permeability coefficient P, defined as the ratio of the transmembrane flux to the concentration jump across it.

I present a metadynamics-based approach to derive an accurate picture of the permeation process and the calculation of P, which allows us to construct a detailed molecular model of the transition state. We construct a multidimensional rate model which takes into account several slow degrees of freedom: position and attitude of the drug relative to the lipid membrane plane, quantities describing desolvation, et cetera. Using this model, we compute the mean permeation time (MPT) through the membrane and derive a formula for computing P in simulations where periodic boundary conditions prevent non-zero flux and concentration jump across the membrane. Then we show that P is directly correlated with MPT, which is explicitly calculated from the rate model.