Atomistic Simulation Studies of the Permeation of Organic Molecules Through Lipid Membranes

Abstract

For drugs with intracellular targets the process of permeation through the membrane is of fundamental importance (A. Malkia, et al., Euro J of Pharm Scien, 23,13-47, 2004). Usually the rate of this process is predicted using QSAR or other knowledge-based predictors (R Gozalbes, et al., Bioorganic & Med Chem,19, 2615-2624, 2011). However, this approach is not always accurate. Moreover, it does not provide the atomistic details of the process, and thus its prediction cannot be directly exploited to rationally design drugs with higher permeation rate. We developed a protocol for studying the permeation of small organic molecules (e.g. drugs) through lipid membranes by atomistic simulations. This protocol allows computing accurately the permeability coefficient, and provides a detailed atomistic picture of the process. The approach is based on an enhanced sampling technique, bias exchange metadynamics (S. Piana and A. Laio, J Phys Chem B, 111, 4553-4559, 2007), that allows deriving from atomistic simulations a multidimensional free energy landscape and an accurate kinetic model describing the transitions between the relevant metastable states of the system (F Marinelli, et al., Plos Comp Biol, 5, e1000452, 2009). As a benchmark, we applied this protocol on the permeation of ethanol through palmitoyloleoylphosphatidylcholine (POPC) membrane. We are applying the same procedure to study the permeation of two anti-HIV drugs where unbiased simulation of the permeation process is not possible.