Polarization effects stabilize bacteriorhodopsin's chromophore binding pocket: a molecular dynamics study.

Hybrid methods, which combine a quantum mechanical description of a chromophore by density functional theory (DFT) with a molecular mechanics (MM) model of the surrounding protein binding pocket, can enable highly accurate computations of the chromophore's in situ vibrational spectra. As a prerequisite, one needs a MM model of the chromophore-protein complex, which allows a correct sampling of its room-temperature equilibrium fluctuations by molecular dynamics (MD) simulation. Here, we show for the case of bacteriorhodopsin (BR) that MM-MD descriptions with standard nonpolarizable force fields entail a collapse of the chromophore binding pocket. As demonstrated by us, this collapse can be avoided by employing a polarized MM force field derived by DFT/MM hybrid computations. The corresponding MD simulations, which are complemented by a novel Hamiltonian replica exchange approach, then reveal a structural heterogeneity within the binding pocket of the retinal chromophore, which mainly pertains to the structure of the lysine chain covalently connecting the retinal chromophore with the protein backbone.