In the light-driven proton pump bacteriorhodopsin, after photoisomerization of the retinal chromophore, a proton is transferred from the retinal Schiff base to the nearby Asp85.
Here, the mechanism of this transfer step is determined by computing minimum-energy reaction paths in the protein using combined quantum/classical mechanics (QM/MM).
The results reveal that the Schiff base donor NH group first orients in the direction opposite to that of the proton transfer. From this stable state, three mechanisms are found to have energy barriers in agreement with experiment:
In one, the proton is transferred directly to Asp85.  In the second, the proton is transferred along a proton wire via Thr89.  In the third, the proton is transferred first to Asp212 and then to Asp85 along a proton wire via a water molecule.
Some of these pathways require considerable twisting of the Schiff base accompanied by displacements of surrounding residues. Given the close proximity of the Schiff base and Asp85 (~4 Angstroem), the coexistence of these very different transfer mechanisms is unexpected.
Alternative pathways in the presence of an additional water (which is hydrogen bonded to retinal on the cytoplasmic side) are also energetically allowed.

 

The absorption of one photon by the all-trans retinal chromophore leads to rotation of the C13-C14 bond into the 13-cis conformation. This triggers a photocycle, the net effect of which is the transfer of one proton from the cytoplasmic to the extracellular side of the membrane. This figure shows the proton transfer steps in bacteriorhodopsin in the order they occur. Step 1 is the "primary" transfer step, from the retinal Schiff-base NH to Asp85.

Several mechanisms are conceivable for primary proton transfer, shown here :  The proton transfers could take place on either side of retinal (green and magenta arrows, respectively) and could be either direct (broken lines), or involve intermediate proton carriers and/or proceed via a proton wire (continuous lines). An exhaustive exploration of these different mechanisms was performed by computing all possible reaction pathways and their transition states with the   Conjugate Peak Refinement (CPR) method.  The three pathways with the lowest energy barrier are shown here:

Path 1a.   Download the movie  (1.2Mb)
Direct proton transfer from the retinal Schiff base to Asp85.
The shortening of the donor-acceptor distance involves significant twisting of the retinal chain and simultaneous displacement of the Asp85 side chain.  Rate-limiting barrrier 12.4kcal/mol.
 

Path 2. Download the movie (0.5Mb)
The Schiff base proton is transferred to the hydroxyl group of Thr89, whose own proton is transferred to Asp85 in a concerted manner.  The initial hydrogen bonds are optimally arranged for this proton wire, such that little change in retinal twisting is needed, which distinguishes this mechanism from the others.  Rate-limiting barrrier 13.6kcal/mol.
 

Path 3a.
Proton transfer to Asp212 followed by proton wire through water w402.

This pathway begins with a conformational change in retinal twisting: Download the movie  (1.1Mb)

The subsequent proton transfer steps take place with little structural rearrangement. First, the Schiff base proton is transferred to Asp212. The hydrogen-bonding pattern around Asp212 then reorganizes to form a proton wire from Asp212 to Asp85 via water w402.  Rate-limiting barrrier 11.5kcal/mol. Download the movie  (2.4Mb)
 

Conclusions
Mechanisms 1a and 3a require extensive flexibility in the retinal chain and neighbouring residues to bring the donor-acceptor distance within proton transfer range.  Because these proton transfer mechanisms involve the complex interplay of many different degrees of freedom in addition to proton displacement, such as retinal twisting and water rotation, the 'a priori' definition of a suitable reaction coordinate is not practical and the use of an automated method like CPR for finding the minimum energy paths is indispensable.  The usefulness of the QM/MM approach is clear in this case, by allowing the donor and acceptor groups of the quantum region to be carried flexibly by the protein scaffold.

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