Computational investigations of membrane proteins have greatly benefi ted from the spectacular increase in computational power witnessed in recent years. In particular, distributing the work load on arrays of processors of massively parallel architectures, molecular dynamics (MD) simulations [1, 2] have played an important role in this research area by handling large assemblies of atoms formed by the protein and its lipid environment -viz. on the order of 10 5 to 10 6 particles [3 -5] . They have contributed to the understanding of the molecular mechanisms whereby these proteins function, whenever their three -dimensional structure was available. In the absence of a well -resolved structure, MD simulations have also helped interpreting inferences accrued from experimental sources, such as structure -activity relationships, or sitedirected mutagenesis.Although MD simulations can offer a detailed, atomic picture of membrane proteins, they span time scales over which relevant biophysical phenomena cannot be easily captured. This can be readily understood by considering the infi nitesimal time step utilized to integrate numerically the equations of motion -viz. on the order of 10 − 15 s, whereas most signifi cant biological processes in membrane proteins occur over the 10 − 6 to 10 − 3 s time scale. Moreover, equilibrium MD simulations are plagued by Boltzmann sampling, which favors low -energy confi gurations, thereby precluding the exploration of regions of phase space separated by appreciable free energy barriers. Noteworthily, whereas the parallelization of MD codes has opened new horizons for exploring complex, sizeable biological systems, it has only moderately increased the time scales over which these systems can be investigated. This explains why coarse -grained approaches [6 -8] have recently become fashionable in the fi eld of theoretical and computational biophysics, removing the fi ne atomic detail to retain only the quintessential structural features of the molecular assemblies.In spite of the fact that MD simulations per se are not capable of capturing rare events characterized by signifi cant free energy barriers, they can be used,
