Shortcuts to new protein folds.

There are some possible shortcuts.
1. The changes that are known to occur which change how specific an enzyme is for a particular reaction thus allowing it to use a slightly different chemical.
These are where a small change in the structure of an existing protein means that it can use a slightly altered substrate.
Examples of this kind of change are the oscillations in the antibiotics battle.
People discover an antibiotic --> microbes die
a microbe develops resistance by a small change in protein structure --> people die
People develop a slightly changed antibiotic --> microbes die.
Etc.
In these cases there is a shortcut to other similar functions by a relatively small number of mutations.
(Usually it is this kind of change that is presented as evidence for evolution.)
Why aren’t this kind of shortcuts sufficient to reassure us that evolution can solve the problem?
Not all proteins have this kind of relationship with each other. Protein databases have 1777 classes of structural domains These are the “superfamilies” of protein structures. There may be recognisable similarities between domains within a superfamily … but the superfamilies themselves are not related.
Even if all the proteins within a superfamily can be derived from one original sequence this does not explain the origin of all the 1777 plus classes of superfamily.
2. If a relatively few changes causes a change in function and this is followed by subsequent sequence divergence in the new protein. Axe considers an example of this from PA Alexander published in PNAS….. and argues that this will not get us very far.
3. If proteins are made up of a relatively small set of “chunks” rather like a lego kit. This would simplify the problem of building a new protein superfamily. Gene fusion events can be used to build a new structure.
But Axe states that…”The binding interfaces by which elements of secondary structure combine to become units of tertiary structure are predominantly sequence dependent, and therefore not generic.”
Thus enzymes with an identical function and 50% sequence similarity do not have chunks which are interchangeable. Even when this similarity is increased to 90% equivalent chunks are not interchangeable. Graziano and his co-workers constructed and tested a huge library of 10^8 variants of gene segments and found none that formed a folded structure.

Axe concludes that all of these putative shortcuts are dead ends. The Darwinian search mechanism is not capable of finding new protein folds by random sampling and all the shortcuts to new folds are dead ends.