The Amazing Natural Order Behind “Random” Protein Folding

In the dynamic evolutionary interplay between order and chance, it is the order that is more fundamental.
This is a companion discussion topic for the original entry at

Back in my high school days when I read apologetics, randomness was the only thing I thought of when I see the term, evolution. Even when I believe that evolution is real, I didn’t know how to answer my friends if they ask me about evolution and “chances”.

I’m glad I’m understanding evolution a little bit better.

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I agree. Dennis it would be good to have a post or two on randomness and evolution. Will the tape produce the same results if replayed based on current knowledge.

Happy to see this point so well made. I’d be curious to hear some thoughts on intrinsically disordered proteins. It seems to me their functionality, reduced constraints, and relative abundance undermine arguments based on protein folding probabilities.


Great post, and very timely. I am writing an article on the work of Andreas Wagner, who has shown that the same activity or phenotype of protein structures, as well as gene regulatory circuits, and metabolic pathways can arise from an enormous number of possible structures and genotypes, some of them quite distant from each other. This concept allows for the simultaneous blossoming of robustness and innovation that underlies evolution. Very exciting developments. Thank you Dennis, for introducing Dan Kuebler and posting his piece for the forum.


You’re in luck - the next post in this series will look at intrinsically disordered proteins in detail. :slight_smile:

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Thanks for this. I have a few follow-up questions:
Why 10^150 sequences? The paper cited shows 20^100 or about 10^130 (actually 10^126 because they say maybe only one in 10^4 adopts a stable structure. Beyond that, the idea behind increasing the probability is clear, but the final probability is unclear (to me at least).

The more important question is regarding human DNA which can be fully represented on a 1.5 GB of data (fits easily on a thumb drive). Clearly so little data cannot fully describe the human organism and its development process. So where exactly is the information for the actual human blueprint? And what implication does this have for your analysis of protein folding?

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That is a very good question. Before completion of the human genome project, almost everyone thought that there must be at least 100,000 genes in humans. Instead there are a bit less than 20,000. That;s fewer genes than in rice, and lot of invertebrates. So what’s going on? We now know that many human genes can be expressed using alternate splicing, so that one DNA sequence can actually code for more than one protein. We also know that for many complex traits, the key factor is differential expression of a suite of genes rather than one gene for every phenotype. In other words, we have learned that the human blueprint, which includes all of human functioning as well as structure is a very complex, interactive process of gene regulation and DNA metabolism. There is nothing simple in biology.

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Variability from the indirect and direct action of the conditions of life, and from use and disuse; a Ratio of Increase so high as to lead to a Struggle for Life, and as a consequence to Natural Selection, entailing Divergence of Character and the Extinction of less improved forms.” - See more at:


I have quoted Darwin as he was quoted in this articles. I agree that this passage is the key to understanding evolution through the eyes of Darwin and I agree with Dr. Keubler that Darwin saw evolution as an orderly process.

However one needs to look at this passage very carefully. Darwin saw evolution as a two step process, 1. Variation, and 2. Natural Selection, and it is the second aspect which is the source of order not the first.

Nonetheless, the modern study of evolution has concentrated on genetic Variation, rather than Malthusian Natural Selection. Some have even claimed that genetic drift negated Natural Selection.

Darwin put more emphasis on NS than Variation. I see the emphasis going far the other way today. I do not want to put down genetics and Variation, but Natural Selection needs equal attention, which it does not get today. This article and the others on this blog bear this out very clearly.

Genetics is not simple and needs study, but then too so is ecology, and it needs study also to determine how it effects evolution.