Nice discussion. I've emailed Chao Tang, the corresponding author.
Hopefully we will be joined by an 'authority figure'.
Meantime, here are my 0.02$:
On Mon, 19 Aug 1996, Simon Brocklehurst wrote:
> "protein structures are selected because they are... stable
> against mutations"
> What kind of mutations are we talking about here?
> Surely, in _general_ proteins are actually NOT stable against
> mutations... and this would be _especially_ true of very
> small proteins e.g. a 27-mer, wouldn't it?
I think there is a misunderstanding of the phrase "stable against
mutations". What this means, IMHO, is that highly designable structures
are likely to remain at the same ground state, or are better off
thermodynamically due to mutations, as opposed to non-highly-designable
structures. This is appended to the observation that highly designable
structures are on the average more thermodynamically stable than less
designable structures. (Fig. 3)
Quote: (Page 668, middle column)
"[given a highly designable structure S]...A mutation of the sequence may
change the energy of the structure S as wel as those of the competing
structures. If the gap is large, it is less probable that the energies of
the competing structures will shift below that of the structure S. Thus
the structure S is likely to remain as the ground state of the mutant"
I think what follows from this is that on the average, a random point
mutation in a sequence leading to a highly-designable structure (HDS) is
less likely to unravel it than a random point mutation in a non-highly
designable structure. (NHDS). (Isn't this actually implicit in the
definition? More sequences encode an HDS than an NHDS?)
Then again, HDS's have more conserved sites. (Fig. 4a). So I may be
missing something here...
> The authors observe that their "designable" structures are characterised
> by having _both_ of the following kinds of sequences:
> 1. sequence families with many conserved positions (i.e.
> conserved H residues, or conserved P residues)
> 2. some sequences completely unrelated to other sequences
> (i.e. statistically insignificant sequence similarity -
> e.g. no positions with conserved H across the family)
> In real proteins however, it seems to me that we see observe something
> fundamentally different: divergently evolved protein families are almost
> always of ONLY type 1 (remember we're not talking real sequence identity,
> rather we're talking conserved "key" residues types). Anyone disagree?
I agree here.
> We tend to observe type 2. sequence relations when comparing _UNRELATED_
> proteins that have the same fold - this is nothing to do with
> divergent evolution though.
Yes. If we wish to draw the evolutuionary case here, we are talking of
convergent evolution. This is corroborated by the observation that only
about ~1000 possible folds exist. I surmise that for a given fold, several
urelated sequences may exist. Anybody know of a work which checks
Keep it going,
Iddo Friedberg ("\''/").___..--''"`-._ Phone: (972)-2-6585459/3 `9_ 9 ) `-. ( ).`-.__.`) email: firstname.lastname@example.org (_Y_.)' ._ ) `._ `. ``-..-' web: http://www.ls.huji.ac.il/~idoerg _..`--'_..-_/ /--'_.' .' More info: finger email@example.com Random quote: If we do not change our direction we are likely to end up where we are headed.