Week 9: The Final Piece of the Puzzle

Aditya L -

Hey everyone,

Thanks for tuning in. Over the past week, I was able to find one of the critical interactions and lend some clarity to the work that I’ve been doing for the past few months now.

But first, heres a brief recap of last week: When there is an empty rhodopsin with no molecules in a solution with both Benzo[A]Pyrene (environmental pollutant) and 11-cis-retinal (the natural human molecule), the Benzo[A]Pyrene first docks to the dark state Rhodopsin, but is prematurely released. This causes the 11-cis-retinal to be expressed despite Benzo[A]Pyrene’s better binding affinity.

I started off this week by creating some residue figures (which basically show a zoomed in interaction of the protein). Interestingly, although Fig 2. for Benzo[A]Pyrene shows more interactions (easier to see in a 3D view), it doesn’t form a Schiff-base linkage with the K296 residue. A Schiff-base linkage is basically a strong attachment interaction which leads to a protonated state, that is ultimately stabilized by some counterion in the protein. Because 11-cis-retinal (Fig. 1) has an aldehyde at the very end, it is able to form a Schiff-base linkage with the Rhodopsin protein’s K296 residue, which means that after the process has concluded, there is also a counterion (113) which stabilizes the 11-cis-retinal and holds it in place. This is why the 11-cis-retinal does not prematurely detach during photo-transduction. On the other hand, despite adopting a stronger binding affinity, B[A]P only contains carbons and is incapable of forming a Schiff-base linkage with K296, so it does not get protonated, and is not able to hold onto any counterions. Biochemically, this means that the B[A]P’s affinity can only get it to interact the dark state, but will almost never naturally be held in the light-state conformation due to premature release.

Now that I have found this interaction, I will be focussing more on the implications next week, as well as a formal recap of my project as a whole.

Sincerely,

Aditya Lakshminarasimhan

A.

Fig 1. 11-cis-retinal human molecule docked to Rhodopsin Lumi state.
B.
Fig 2. Benzo[A]Pyrene environmental pollutant docked to Rhodopsin Lumi state.

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Comments:

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    alisha_j
    Hi Aditya! This is a very interesting finding. I am fascinated to know how the 11-cis-retinal vs the B[A]P causes such unique and different results. It reminds me of the "lock-key" concept and the differences in protein transformation due to misfolding that we learned in AP Biology.
    April 13, 2025 at 11:25 am - Reply
      aditya_l
      Hey Alisha, thanks for reading, and you're absolutely right! Despite both molecules fitting the Rhodopsin protein, small differences prevent one from staying in place.
      April 17, 2025 at 1:04 pm - Reply
    evangeline_c
    Fascinating work! Would you expect a similar binding behavior if other environmental pollutants with different structures were tested, or is this interaction specific to B[A]P?
    April 14, 2025 at 9:51 am - Reply
      aditya_l
      Hey Evie, that's a great question. That is definitely something that I would like to test. One thing to note, however, is that Benzo[A]Pyrene is one of the more prevalent molecules in fire sites (which was one of the reasons for choosing it), and it is optimized to have a smaller shape. Some other variants of Pyrene will include an extra branch, that moves the main Benzene rings out of place. It is definitely something I will consider as a future project, but for the scope of this project, Benzo[A]Pyrene met many criteria as a 'model system.'
      April 17, 2025 at 1:07 pm - Reply
    mikyle_h
    Hey Aditya, thanks for the update! I had a quick question: even though Benzo[A]Pyrene can’t form the Schiff-base with K296, do you think it could still affect how rhodopsin works just by being there first?
    April 15, 2025 at 10:30 pm - Reply
      aditya_l
      Hey Mikyle, thanks for the question! Because B[A]P is unable to form the Schiff-base, it will inevitably be outcompeted by 11-cis-retinal in the presence of light. However, in low-light conditions, where the 11-cis-retinal does not change shape into all-trans-retinal, the B[A]P could definitely interfere competitively and cause discoloration to the eye.
      April 17, 2025 at 1:10 pm - Reply

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