Chapter 21:Investigating Mechanisms of Ligand Recognition, Activation and Oligomerization in GPCRs Using Enhanced Molecular Dynamics Methods

GPCRs mediate biological processes on timescales of the order of seconds-to-minutes. Currently, sophisticated molecular dynamics (MD) programs (e.g. Desmond, NAMD and GROMACS) adapted to massively parallel computer architectures (e.g. Blue Gene and Anton) have allowed execution of microsecond-scale standard MD simulations of fully atomistic representations of GPCRs embedded into explicit lipid–water environments. However, average experimental timescales for key events in the life-cycle of GPCRs, such as ligand binding/recognition, activation and oligomerization, remain far from being reached. The situation is further complicated by the stochastic nature of these biological processes and the obvious limitations of classical MD simulations, mainly owing to imperfect forcefields. Several approaches have been proposed to overcome these limitations. Enhanced methods within the framework of classical MD and/or using highly simplified physical models are surveyed here with an emphasis on the results obtained by their application to GPCRs.