Retinal Conformation Governs pKa of Protonated Schiff Base in Rhodopsin Activation

Zhu, Shengshuang; Brown, Michael F.; Feller, Scott E.

doi:10.1016/j.bpj.2012.11.663

Cited by 11 publications

(12 citation statements)

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“…The b-ionone ring remains essentially fixed during the polyene chain rotation, with a transition from 6-s-cis in the starting structure to 6-strans. It has been shown that the 6-s-trans conformation raises the pK a of the SB, favoring the protonated state (13), as in Meta-I. Moreover, the pathway that occurs from cis to trans is very similar to the one observed in previous longtimescale MD studies that examined the dark / Meta-I transition (11,12).…”

supporting

confidence: 52%

“…In particular, the distribution of the dihedral angle for the C6-C7 bond connecting the b-ionone ring to the polyene chain correlates well with previous studies that identified three minima for retinal with a protonated SB (Figs. 1, f and g, and S2) (13). The final orientation of the b-ionone ring is the 6-s-trans conformation, a local minimum for the C5¼C6-C7¼C8 dihedral.…”

mentioning

confidence: 99%

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Retinal Flip in Rhodopsin Activation?

Feng

Brown

Mertz

2015

Biophysical Journal

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Rhodopsin is a well-characterized structural model of a G protein-coupled receptor. Photoisomerization of the covalently bound retinal triggers activation. Surprisingly, the x-ray crystal structure of the active Meta-II state has a 180° rotation about the long-axis of the retinal polyene chain. Unbiased microsecond-timescale all-atom molecular dynamics simulations show that the retinal cofactor can flip back to the orientation observed in the inactive state of rhodopsin under conditions favoring the Meta-I state. Our results provide, to our knowledge, the first evidence from molecular dynamics simulations showing how rotation of the retinal ligand within its binding pocket can occur in the activation mechanism of rhodopsin.

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supporting

confidence: 52%

mentioning

confidence: 99%

Retinal Flip in Rhodopsin Activation?

Feng

Brown

Mertz

2015

Biophysical Journal

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“…The CHARMM36 force field 45 was used for the protein, lipids, and ions. Parameters for retinal bound to lysine were adapted from 46 .…”

Section: Molecular Dynamics Simulationsmentioning

confidence: 99%

Molecular mechanism of light-driven sodium pumping

Kovalev

Astashkin

Gushchin

et al. 2020

Preprint

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ABSTRACTMicrobial rhodopsins appeared to be the most abundant light-harvesting proteins on the Earth and are the major contributes to the solar energy captured in the sea. They possess highly diverse biological functions. Explosion of research on microbial rhodopsins led to breakthroughs in their applications, in particular, in neuroscience.An unexpected new discovery was a Na+-pumping KR2 rhodopsin from Krokinobacter eikastus, the first light-driven non-proton cation pump. A fundamental difference between proton and other cation pumps is that non-proton pumps cannot use tunneling or Grotthuss mechanism for the ion translocation and, therefore, Na+ pumping cannot be understood in the framework of classical proton pump, like bacteriorhodopsin. Extensive studies on the molecular mechanism of KR2 failed to reveal mechanism of pumping. The existing high-resolution structures relate only to the ground state of the protein and revealed no Na+ inside the protein, which is unusual for active ion transporters.KR2 is only known non proton cation transporter with demonstrated remarkable potential for optogenetic applications and, therefore, elucidation of the mechanism of cation transport is important. To understand conception of cation pumping we solved crystal structures of the functionally key O-intermediate state of physiologically relevant pentameric form of KR2 and its D116N and H30A key mutants at high resolution and performed additional functional studies.The structure of the O-state reveals a sodium ion near the retinal Schiff base coordinated by N112 and D116 residues of the characteristic (for the whole family) NDQ triad. The structural and functional data show that cation uptake and release are driven by a switching mechanism. Surprisely, Na+ pathway in KR2 is lined with the chain of polar pores/cavities, similarly to the channelrhodopsin-2. Using Parinello fast molecular dynamics approach we obtained a molecular movie of a probable ion release.Our data provides insight into the mechanism of a non-proton cation light-driven pumping, strongly suggest close relation of sodium pumps to channel rhodopsins and, we believe, expand the present knowledge of rhodopsin world. Certainly they might be used for engineering of cation pumps and ion channels for optogenetics.

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“…The minimization and equilibration protocol involves six steps that gradually remove restraints from the protein backbone, lipids, water molecules, and ions over 375 ps (36). Retinal force field parameters were obtained from Scott Feller (42,43). After equilibration, the systems and force fields were converted to formats compatible with Assisted Model Building with Energy Refinement (AMBER) in CHAMBER (44), and all production simulations were run with AMBER 12 and AMBER 16 packages with graphics processing unit acceleration (45,46).…”

Section: Equilibrium MDmentioning

confidence: 99%

Allosteric Effects of the Proton Donor on the Microbial Proton Pump Proteorhodopsin

Faramarzi

Feng

Mertz

2018

Biophysical Journal

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Proteorhodopsin (PR) is a microbial proton pump that is ubiquitous in marine environments and may play an important role in the oceanic carbon cycle. Photoisomerization of the retinal chromophore in PR leads to a series of proton transfers between specific acidic amino acid residues and the Schiff base of retinal, culminating in a proton motive force to facilitate ATP synthesis. The proton donor in a similar retinal protein, bacteriorhodopsin, acts as a latch to allow the influx of bulk water. However, it is unclear if the proton donor in PR, E108, utilizes the same latch mechanism to become internally hydrated. Here, we used molecular dynamics simulations to model the changes in internal hydration of the blue variant of PR during photoactivation with the proton donor in protonated and deprotonated states. We find that there is a stark contrast in the levels of internal hydration of the cytoplasmic half of PR based on the protonation state of E108. Instead of a latch mechanism, deprotonation of E108 acts as a gate, taking advantage of a nearby polar residue (S61) to promote the formation of a stable water wire from bulk cytoplasm to the retinal-binding pocket over hundreds of nanoseconds. No large-scale conformational changes occur in PR over the microsecond timescale. This subtle yet clear difference in the effect of deprotonation of the proton donor in PR may help explain why the photointermediates that involve the proton donor (i.e., M and N states) have timescales that are orders of magnitude different from the archaeal proton pump, bacteriorhodopsin. In general, our study highlights the importance of understanding how structural fluctuations lead to differences in the way that retinal proteins accomplish the same task.

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Retinal Conformation Governs pKa of Protonated Schiff Base in Rhodopsin Activation

Cited by 11 publications

References 0 publications

Retinal Flip in Rhodopsin Activation?

Retinal Flip in Rhodopsin Activation?

Molecular mechanism of light-driven sodium pumping

Allosteric Effects of the Proton Donor on the Microbial Proton Pump Proteorhodopsin

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