zharkikh at GSBS18.GS.UTH.TMC.EDU zharkikh at GSBS18.GS.UTH.TMC.EDU
Fri Jul 1 16:24:53 EST 1994

Peter Gegenheimer from University of Kansas writes:

>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!

Not exactly!

Thermodynamics disregards FUNCTIONALITY of biological molecules.
Of course, very stable molecules may be biologically DEAD.
That is why, for example, many rRNAs have large proportion G-T pairs.
But so are very unstable molecules. Natural selection balances
between these two cases, producing molecules with a FEW stable
conformations. And they are really STABLE from thermodynamic point.
The reason why folding algorithms cannot find them is only in their
weak recognition power (as any statistical method with enormous
amount of parameters). Another (of many) possibility is that the 
optimal structure may be result of interaction of several molecules,
which is never taken into account in algorithms of folding a single


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