The availability of the structure of bacteriorhodopsin from electron microscopy studies has opened up the possibility of exploring the proton pump mechanism of this protein by means of molecular dynamics simulations. In this review we summarize earlier theoretical investigations of the photocycle of bacteriorhodopsin including relevant quantum chemistry studies of retinal, structure refinement, molecular dynamics simulations, and evaluation of pKa values. We then review a series of recent modeling efforts which refined the structure of bacteriorhodopsin adding internal water, and which studied the nature of the J intermediate and the likely geometry of the K590 and L550 intermediates (strongly distorted 13‐cis) as well as the sequence of retinal geometry and protein conformational transitions which are conventionally summarized as the M412 intermediate. We also review simulations of the photocycle of light‐adapted bacteriorhodopsin at T=77 K and of the photocycle of dark‐adapted bacteriorhodopsin, both cycles differing from the conventional photocycle through a nonfunctional (pure 13‐cis) retinal geometry of the corresponding K590 and L550 states. The simulations demonstrate a potentially critical role of water and of minute reorientations of retinal's Schiff base nitrogen in controlling proton pumping in bR568; the simulations also indicate the existence of heterogeneous photocycles. The results exemplify the important role of molecular dynamics simulations in extending investigations on bacteriorhodopsin to a level of detail which is presently beyond experimental resolution, but which needs to be known to resolve the pump mechanism of bacteriorhodopsin. Finally, we outline the major existing challenges in the field of bacteriorhodopsin modeling.
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