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Imaginary protein nanodevices #1

Simple nanodevice - coiled-coil and leucin-rich-repeat protein

This post starts a series devoted to imaginary nanodevices made of proteins. I’m going to play around with known protein structures to see if some of them can form an interesting arrangement. Basic requirement is lack of obvious sterical clashes at the level of a main chain trace. If that is fulfilled I would assume very slight chance that particular arrangement is possible. However, in most cases I won’t bother inventing how to recreate it in the lab, since I don’t feel competent enough. The whole series is more fiction than science and my goal is mainly stretching my and readers imagination.

Lets start with something simple. Structure depicted above is a dimer of leucin rich repeat (LRR) protein (PDB: 1A4Y, chains A and D) with a trimeric coiled-coil (my own model made with BeammotifCC) fitted in. The opening is wide enough to accommodate three helices without any problems. Picture below shows main chain trace of the coiled-coil (in red) surrounded by LRR dimer (all atoms, blue and sea green). As you can see, any coiled-coil made of aminoacids with small side chains would not create any sterical issues. In fact, approximate size of the opening (~35 Angstroms) is much larger than the opening size of the membrane anchor of trimeric autotransporter adhesins (twelve stranded beta-barrel, PDB: 2GR7), which also accommodates a trimeric coiled-coil. So why not to use a beta-barrel instead of LRR? Well, beta-barrels are hardly present outside membranes 🙂 .

Simple nanodevice - coiled-coil and leucin-rich-repeat protein

One can ask question if the single LRR protein can make a full ring. It looks possible from the structure of the single repeat (beta-turn-alpha) – interactions with preceding and following repeats are virtually the same. However, secondary structure elements of these repeats are not perfectly aligned with the axis of the opening. Their tilt forces consecutive repeats to form an imaginary spiral, not a circle (although the tilt does not seem to be large enough to actually allow for spiral folding of larger number of repeats – but that’s only my assumption, it would be worth to check).

So that’s it for now. If you feel that I’m rediscovering wheel, writing something completely silly, or you have any suggestions, please feel free to discourage/encourage me with comments.

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Posted by on January 21, 2008 in Imaginary nanodevice, Proteins, Structural biology

 

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Tracking changes in a multiple sequence alignment

I had few free hours during this weekend so I’ve hacked together couple of scripts that in theory could help me visualize changes between subfamilies in the protein multiple sequence alignment. In essence, I took the alignment, chose a master sequence that correspond to a known structure, removed all columns with gaps in the master sequence, and visualized fragments of the alignment (sliding window with 15 sequences) with Weblogo – software for preparing sequence logos from alignments. On the video below you can see:

  • two boxes showing the same template structure (second is just rotated); size of C-alpha atoms correspond to overall conservation at that position; first few residues do not have corresponding positions in the alignment
  • sequence logo of actual alignment window
  • sequence logo of the whole alignment – as a reference

There are several of things I’m not yet happy with. First of all, visualization of changes on the structure is hardly readable, even with video of much higher quality (probably I should do it with Chimera’s “worm” representation). Second thing is that I have no information which species/proteins I’m looking right now at (another box with highlights on a species tree of the family?). Also, I should remove some redundancy from the alignment; sometimes sliding window contains copies of the same protein. But overall it looks promising enough to convince me to spend few more hours on this small project. However, I would probably do the final version with Processing.

 
 

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Thoughts on CASP – Critical assessment of methods of protein structure prediction

I’ve just read an introduction to the supplemental issue of the journal PROTEINS, dedicated to the most recent round of the CASP experiment. It describes the progress of the protein structure prediction over the last few CASP editions.

The list of advancements include:

  • improvement of the homology modelling: one of the issues in template-based modelling of protein structures was that a final model wasn’t closer to the real structure than a template; now we have statistically significant (although very small) improvement thanks to the multi-template based modelling
  • fully automated methods are much closer to human predictors than ever: many groups use models from servers as their starting point and usually they don’t improve them that much

I believe that this was possible thanks to the progress that has been made in the area of sequence homology searches. Finding similarity between two sequences well beyond any reasonable identity thresholds is now doable thanks to profile-to-profile comparison, meta-servers (joining predictions from many different methods) or recent hmm-to-hmm algorithms (comparison of Hidden Markov Models). If you can find a suitable template for your protein, the rest is then much easier, isn’t it?

There are of course fields that still need some work. One of these often stirs a lot of discussion: automated assessing of model similarity to the real structure. The current methods have proven their suitability, I definitely agree. However I hope that at some point the protein structure comparison software will refuse to superimpose eight- and ten-stranded beta-barrels or left- and right-handed coiled-coil with a message: “It doesn’t make sense.”

CASP 7 logo

 
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Posted by on October 10, 2007 in Comments, Papers, Research, Structure prediction

 

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