Match and Mix: The difference between Rational Design and Combinatorial Chemistry

Hello Everyone,

I wanted to share a some thoughts I had after taking a hiking trip to the South Mountain Reserve this weekend.  I came across this peculiar tree on the trails:


As you can see, the tree appears to grow in one direction, take a U-turn, but then continue growing in the same direction!  This tree reminded me of the two different fundamental approaches to creating new biomolecules: Rational Design and Combinatorial Chemistry.  To highlight the differences I’ll share an excerpt from my thesis about a story I once heard:

“The drawbacks in peptide rational design and the merits of synthetic molecular evolution were illustrated to me in a thought experiment by Dr. Chris Moser.  Suppose that there is a river crossing wherein three rocks exist to allow people to cross the river (A).  After some time, a wooden plank is placed over top of these rocks, improving the ability of people to cross the river(B).  After even more time assume the rock in the middle floats away or is removed such that the plank is suspended across only two rocks (C).

Rational Design Example

Now, if a passerby came to the river now they would notice that removing any one component of the bridge, either one of the rocks or the plank, would prevent someone from crossing the river.  New passersby might conclude that the bridge has to exist in this conformation otherwise it could not function, but they will miss the fact that a scaffold existed beforehand which allowed for the same function.  This is the case with rational design. We miss key insights and understandings of our bridges; our peptides; when we attempt to jump directly to what we perceive to be the structure-function relationship.”

Who can say why this tree took this route of growth?  We might be missing something in assuming that this was the optimal or best “tree design” rather than creating a synthetic evolutionary process to see what shape it takes.  I won’t say that one method is better than the other, both have their merits.  I will leave you with this thought that the task of creating new molecules can often be more complex than it  appears on the surface.

Thanks for reading,



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