Simulation of the Functional Dynamics of Bacteriohodopsin in the Integral Purple Membrane

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SchultenMCB 9982629Vectorial proton translocation through membranes is a fundamental energy conversion process in biological cells. Bacteriorhodopsin (bR) is a membrane protein that acts as a light-driven, voltage sensitive proton pump in the purple membrane (PM) of Halobacterium salinarium and achieves its biological function by cycling through a reaction that includes ultrafast (~ 500fs), intermediate (micro), and slow (~10ms) processes in its photo-cycle. The simulation of the photo-process and the first intermediates of bR's photo-cycle in the integral PM will be carried out in order to explain the pump mechanism. Internal water that participates in proton pumping is fundamental for an understanding of the function of bR. Several water molecules have been resolved now crystallographically. Free energy perturbation theory has also been used to successfully place water molecules in bR in modeling studies. Simulations have also revealed that water molecules become displaced during the photo-cycle. The latter calculations depend on the quality of the force fields for water-peptide interactions that still need to be improved. This project will (i) use molecular dynamics (MD) tools and build a realistic model of the PM, including all of its protein, lipid and water components; (ii) apply a new generation of water-peptide potentials to describe bR's internal water; (iii) use the PM model to investigate through MD simulations the influence of hydration on structural properties of the PM; (iv) furnish multiple potential energy surfaces for the retinal chromophore of bR in the ground and excited state, as a function of relevant internal coordinates and including conical intersection to the ground state; (v) carry out quantum dynamical calculations of the primary photoreaction; and (vi) characterize the photocycle intermediates K, L and M using classical molecular dynamics simulations.Bacteriorhodopsin is of utmost simplicity in comparison with other proton translocating bioenergetic proteins and, therefore, constitutes an ideal model for the study of the reaction process. The purple membrane of Halobacterium salinarium involves a highly structured supramolecular organization, and is fundamental for the in vivo functioning of Bacteriorhodopsin.