Molecular Simulations Distinguish Rhodopsin Counterion Models by Retinal Polyene Fluctuations

Abstract

We investigated retinal conformational changes within the binding cavity of rhodopsin through all-atom molecular dynamics (MD) simulations on the microsecond time scale. Two distinct pathways involving post-isomerization release of retinal conformational strain were tested. The MD trajectories for the counterion-switch and complex-counterion mechanisms [1] show that retinal experiences completely distinct geometrical rearrangements, yielding differences in its orientation and conformation. In the counterion-switch simulation the dihedral angle C11=C12-C13=C14 fluctuates, and is correlated with changes in the C5-, C9-, and C13-methyl group orientations with respect to the membrane normal. For the complex-counterion simulation, changes in the dihedral angle C7=C8-C9=C10 allow the methyl group orientation to remain relatively unaffected (∼60° for the C5-, C9-, and C13-methyl groups), consistent with 2H NMR data [2,3]. The C5=C6-C7=C8 and C9=C10-C11=C12 torsion angles also experience significant fluctuations, but at different times in each counterion simulation and not in conjunction with retinal methyl re-orientation. In addition to retinal polyene chain analysis, the calculated 2H NMR spectra from each simulation clearly demonstrate that the retinal methyl orientations for the complex-counterion mechanism accurately reproduce experimental 2H NMR data for Meta I [2,3], whereas the counterion simulation does not. Rhodopsin simulations on the microsecond time scale are essential for modeling rhodopsin activation up to the Meta I photointermediate, because retinal polyene chain fluctuations occur as late as ∼1500 ns into each simulation. This work builds on our previous computational studies examining rhodopsin in the dark and Meta I states [1,4] and provides valuable insights into the rhodopsin activation process. [1] K. Martínez-Mayorga et al. (2006) JACS128, 16502-16503. [2] G.F.J. Salgado et al. (2006) JACS128, 11067-11071. [3] A.V. Struts et al. (2007) JMB372, 50-66. [4] P.-W. Lau et al. (2007) JMB372, 906-917.