🚀 go-pugleaf

In <SRE.94Jun30074507@al.cam.ac.uk>, sre@al.cam.ac.uk (Sean Eddy) writes:
>In article <2ut37o$h9a@tierra.santafe.ede> stadler@SantaFe.edu (Peter Stadler) writes:
>  >We have been successfully folding 23S RNAs on an IBM RISC 6000/550
>  >with 64MByte memory and the complete genome of the phage Qbeta on
>  >an maschine with 256MByte. 
>
>By successfully, do you mean "the computer didn't crash in a swap
>storm", or "I got the right answers"? I suspect the first.  My advice
>to someone wanting to fold a single molecule of 2.5 kb of RNA is
>"don't do it". (If you have multiple RNAs, and you're using RNA
>folding programs as a first-pass tool to help you look for a structure
>they all share, that's a different story.) RNA folding programs
>sometimes mis-predict 75 nt tRNA structures; I don't think I've seen
>one ever get a 400nt group I intron right; and I don't even want to
>think about a 2.5 kb molecule.
>
>You can look at suboptimal foldings from Michael Zuker's algorithm and
>say you succeeded because the presumed correct structure is within x%
>of the global minimum, but you can only say that because you know the
>correct structure (say, from comparative sequence analysis).  If
>you're dealing with a new structure, how do you pick the correct guy
>out of the haystack of suboptimals?
>
>The level of faith in RNA secondary structure prediction is sometimes
>shocking:
>
>"The credibility of the resulting structures did not seem to be an
>issue. There is even an unsubstantiated rumor (worth repeating) that
>when Brosius, Noller, and their colleagues submitted the first 16S
>rRNA sequence for publication, one of the reviewers questioned why
>they had not included the molecule's secondary structure as well!"
>             - Woese and Pace, in _The RNA World_, CSH Press, 1993
>
>--
>- Sean Eddy
>- MRC Laboratory of Molecular Biology, Cambridge, England
>- sre@mrc-lmb.cam.ac.uk

!!!   * A * M * E * N *   !!!

The optimal folding(s) of any biological macromolecule is(are) the one(s)
which produce a FUNCTIONAL molecule. For most enzymes and other RNAs and 
proteins, the global energy minimum structure is by definition a DEAD molecule,
since most functional molecules must cycle between several different 
conformations during a round of catalysis, etc.

As any RNA biologist can tell you, a purely thermodynamics-driven folding 
algorithm is guaranteed to give the WRONG answers -- that's why all CORRECT RNA
secondary structures to date (from tRNA to RNase P to Group I introns to 
16S and 23S rRNA) were determined by phylogenetic comparison!

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