biomolbioandco

Science, discussed.

[review] Computational stability analysis to reveal functional hotspot?

I was reading the following paper

Stability-activity tradeoffs constrain the adaptive evolution of RubisCO
Romain A. Studer, Pascal-Antoine Christin, Mark A. Williams, and Christine A. Orengo
PNAS 2014 111 (6) 2223-2228
http://dx.doi.org/10.1073/pnas.1310811111

When the possible implications of figure 2 captured my attention:

Figure 2 From Studer et al, PNAS 2014. Click on figure for original

Indeed, it suggests that looking for stability can reveal much about function. The blue bars in panel A indicate positions that can easily be stabilised by mutation (when virtual, full randomisation is conducted on the whole sequence). However, panel B shows that very few of these positions are ever mutated in members of the protein family.

I thus suspect that these positions ‘constrained’ in a sub-optimal residue are essential for function. And that comparing stability values for ‘theoretical’ and ‘natural occurring’ variants might provide an easy detection method.

What do the authors and others think? Worth trying out on more systems?

BTW, the paper is very much worth reading even beyond Figure 2!


Post-publication comments cross-refs: Pubmed Commons, PubPeer

Advertisements

About Pietro Gatti

Interested in discussing (good) Science Lover of coffee & good films. Ideas all & only my own.

2 comments on “[review] Computational stability analysis to reveal functional hotspot?

  1. Romain Studer
    22/05/2014

    Dear Pietro,

    Thank you for this review. I agree with your comment. These positions in blue are generally position that are participating in the function, by either binding the ligand or by catalysing other reactions.

    These two papers have already explored such trends, in the relationship of functional residues and their destabilising effect on the protein:

    How Protein Stability and New Functions Trade Off.
    Nobuhiko Tokuriki, Francois Stricher, Luis Serrano, Dan S Tawfik
    http://www.ploscompbiol.org/article/info%3Adoi%2F10.1371%2Fjournal.pcbi.1000002

    Relating destabilizing regions to known functional sites in proteins
    Benoît H Dessailly, Marc F Lensink and Shoshana J Wodak
    http://www.biomedcentral.com/1471-2105/8/141

    Best regards,
    Romain

    • @p_gl
      22/05/2014

      Hi Romain,
      Thanks for your reply.
      The assumption that destabilising positions are functionally relevant is indeed not new and has been tested before (although I have to admit I didn’t know the Dessailly et al paper…). What I found in your paper that I hadn’t seen before is the correlation between the (predicted) flexibility profile of all possible mutants and of that of naturally-occurring variants.
      This differences provides more information about ‘function’ than the simple analysis of the stability effects of mutations (e.g. reveals which positions are under selective constrains).

      best

      Pietro

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s

License

Creative Commons License
This blog is licensed under a Creative Commons Attribution 3.0 License.

Archives

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 1,560 other followers

All Categories

%d bloggers like this: