Two Relations to Estimate Membrane Permeability Using Milestoning

• DOI: 10.1021/acs.jpcb.6b02814
• Publication Date: 2016-05-07T08:21:53Z
• Authors: Lane W. Votapka; Christopher T. Lee; Rommie E. Amaro
• Keywords: Diffusion; Models, Molecular; Narcotics; 0301 basic medicine; 03 medical and health sciences; Cell Membrane Permeability; Codeine; Lipid Bilayers; Urea; Computer Simulation; Algorithms; Permeability

Prediction of passive permeation rates of solutes across lipid bilayers is important to drug design, toxicology, and other biological processes such as signaling. The inhomogeneous solubility-diffusion (ISD) equation is traditionally used to relate the position-dependent potential of mean force and diffusivity to the permeability coefficient. The ISD equation is derived via the Smoluchowski equation and assumes overdamped system dynamics. It has been suggested that the complex membrane environment may exhibit more complicated damping conditions. Here we derive a variant of the inhomogeneous solubility diffusion equation as a function of the mean first passage time (MFPT) and show how milestoning, a method that can estimate kinetic quantities of interest, can be used to estimate the MFPT of membrane crossing and, by extension, the permeability coefficient. We further describe a second scheme, agnostic to the damping condition, to estimate the permeability coefficient from milestoning results or other methods that compute a probability of membrane crossing. The derived relationships are tested using a one-dimensional Langevin dynamics toy system confirming that the presented theoretical methods can be used to estimate permeabilities given simulation and milestoning results.