[Development of Membrane Permeability Coefficient by Means of Novel Molecular Dynamics Methods]

The membrane permeability, and its evaluation, is crucial factor in the process of uptake of compounds from outside to inside the cell and in the inhibition of the activity of disease-causing target proteins. Although molecular dynamics (MD) simulations have been shown to be able to reproduce the conformational changes of compounds occurring during membrane permeation, it is still challenging to extract the membrane permeability at an affordable computational workload solely by conventional MD. Indeed, the time scale accessible by MD is far below the one characterizing the actual permeation process. Phenomena occurring in living organisms escaping the reach of standard MD are generally referred to as biological rare events, and the membrane permeation process is one of them. To overcome this time-scale problem, several enhanced sampling methods have been proposed over the years to improve conformational sampling. In this review, a hybrid sampling method that combines the parallel cascade selection MD (PaCS-MD) and the outlier flooding method (OFLOOD), introduced and developed by our group, is proposed as a tool to study the membrane permeation from structural sampling (rare-event sampling). The obtained trajectories are used to estimate the free energy profiles for the membrane permeation and to compute the membrane permeation coefficients. Moreover, we present an example of application of the free energy reaction network method as a versatile way for incorporating explicitly into reaction coordinates the degrees of freedom related to internal motion.