The Amazing Natural Order Behind “Random” Protein Folding

| By (guest author) on Letters to the Duchess

All amino acids have a common structure, as well as one chemical group that is distinct. This distinct group can be abbreviated as an “R” to emphasize the chemistry common to all amino acids. Image credit: Wikipedia.

INTRO BY DENNIS: Today I am pleased to introduce my friend and colleague Dr. Dan Kuebler to our readership. Dan is a talented biologist and gifted thinker whom I had the pleasure of getting to know over the last two summers as a member of the Scholarship and Christianity in Oxford (SCIO) Bridging the Two Cultures group of scholars. While there, Dan gave a presentation on protein structure and folding as it pertained to claims made by the Intelligent Design (ID) movement, and I invited him to consider writing a post for BioLogos on the subject. As we saw in the last post in this series, the fundamental chemistry of amino acids drives the formation of alpha helices and beta sheets in proteins. This property, as Dan discusses below, contributes to a relatively small number of possible protein folds that seem to occur at a high enough frequency for evolution to find – further showing that ID claims to the contrary are mistaken.

“There is grandeur in this view of life, with its several powers, having been originally breathed by the Creator into a few forms or into one; and that, whilst this planet has gone circling on according to the fixed law of gravity, from so simple a beginning endless forms most beautiful and most wonderful have been, and are being evolved.”

This line, from the concluding paragraph of Darwin’s Origin of Species, is one of the book’s most widely cited passages. Given the theistic implications coupled with the poetic nature of this passage, the frequency of its citation is not surprising. However, if one were to pick a line that most adequately summed up Darwin’s thoughts on the nature of the evolutionary process, it would not be this famous passage. Rather, it would be the lines that immediately precede this passage.

“It is interesting to contemplate a tangled bank, clothed with many plants of many kinds, with birds singing on the bushes, with various insects flitting about, and with worms crawling through the damp earth, and to reflect that these elaborately constructed forms, so different from each other, and dependent upon each other in so complex a manner, have all been produced by laws acting around us. These laws, taken in the largest sense, being Growth with reproduction; Inheritance which is almost implied by reproduction; 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.”

What makes this passage representative is that it follows a theme that runs throughout the entire Origin, one in which Darwin places particular emphasis on the law-like qualities that govern biology in general and evolution in particular. These “laws impressed upon matter”—as Darwin called them— were both at the heart of scientific discovery and at the heart of his theory.

Too often evolutionary theory is popularized as a random contingent process that cobbles together chance variations into whatever happens to work. Atheistic Darwinists love to point this out when they argue that evolution demonstrates we inhabit a world devoid of any purpose or design. But it is important to remember, as Darwin did, that this chance variation operates on a bed of order—on the “laws impressed upon matter.” In the dynamic evolutionary interplay between order and chance, it is the order that is more fundamental. In fact, it is the order that both shapes and directs the manner by which chance variations are able to build evolutionary novelties.

Nowhere is this more evident than in the process of protein evolution. At first glance, the possibility of a Darwinian process stumbling upon a functional protein seems to be exceedingly unlikely. The odds seemed to be stacked against evolution. To illustrate this, one needs to examine the chemical composition of proteins. Biological proteins are strings of amino acids connected together by chemical bonds. Just like letters can be arranged to produce sentences, amino acids can be arranged to produce proteins. Because there are twenty possible amino acids, a specific functional protein that is 100 amino acids long represents just one possibility amongst a total of 10150 sequences. (To put this number in perspective there are only 1085 fundamental particles in the universe.) This represents an enormously vast space. In fact, Intelligent Design[1] advocates argue that this space is so vast that a random search through it could have never stumbled upon a distinct functional protein. The problem with this argument though is that it ignores the underlying chemical and physical order.

When amino acids are joined together into proteins, the various R groups are not involved. Image credit: Wikipedia.

To illustrate the importance of this order, one need only look at how proteins fold. For most proteins to function effectively, they must take on a relatively specific three-dimensional structure. Given that there is a near infinite array of possible amino acid sequences, one might think that proteins could fold into a vast variety of stable structures. This, however, is not the case. In fact, when chains of amino acids start to fold, they collapse into mainly two distinct secondary structures, beta-sheets and alpha helices. Some proteins collapse into a number of alpha helices, others into a number of beta sheets,  and still others into a combination of the two. They do this because these are the chemically stable structures for chains of amino acids when they are put into the cellular environment. A huge array of amino acid sequences fold into these identical structures, not because natural selection was lucky enough to find them in a random search, but rather because the ordered chemical rules that govern the interactions between atoms and molecules dictates this outcome.

While each of the twenty biological amino acids has a different side chain (R group) that sticks off of it, all amino acids are composed of the same nitrogen-carbon-carbon backbone. When they are strung together in proteins, all the amino acids have a hydrogen sticking off the nitrogen, N-H, and an oxygen sticking off the second carbon, C=O. It is the regularity and limitations of the rotations about these bonds of the backbone (the phi and psi angles) coupled with the need for the hydrogens and oxygens sticking off the backbone to interact that drives the formation of the alpha helices and beta-sheets. In other words, secondary structures arise from the underlying chemical and physical order that is common to all chains of biological amino acids; they are not dependent on specific rare sequences of amino acids. As a result, if evolution were to run again (using the same physics and chemistry), beta-sheet and alpha helices would certainly form in abundance, provided that amino acids were strung together in a chain.

Furthermore, these beta sheets and alpha helices that exist within proteins can only interact with each other in limited ways. This is due to the underlying chemistry and flexibility of proteins. There are only certain ways you can stably stack beta-sheets or loop around alpha helices. As a result, proteins fold into a rather limited array of 3-D structures despite there being a vast array of amino acid sequences. The degree of convergence is staggering. Current estimates suggest that only 1000 to 2000 different 3-D structures seem to be possible. [2]

As biologist Michael Denton succinctly puts it, there are “a number of organization rules, ‘laws of form,’ which govern the local interactions between the main structural submotifs [the alpha helices and beta sheets for example] have been identified, and these restrict the spatial arrangement of amino acid polymers to a tiny set of about 1000 allowable higher-order architectures.”[3] Re-run evolution again with the same chemistry and physics, and the same folds would appear, because the forms of the folds are given by physics and matter is drawn by a process of free energy minimization into the complex form of the native conformation.

To form one of the 1000 or so folds that Denton refers to, one might suppose that it would require a highly specified rare sequence. That doesn’t appear to be the case, however. In fact, there are many cases in which proteins with no sequence similarities fold into the exact same 3D structure. Why? Because the chemical and physical order dictates the stability and commonality of alpha helices and beta sheets and so these form at a significant frequency in any random amino acid sequence.

Suppose that to get a specific 3D fold, one needs to have a beta sheet of a specific length and orientation in a specific location. Given that beta sheets are what amino acids commonly tend to fold into for chemical reasons, evolution does not have to stumble blindly on one specific sequence. It simply has to find any one of the multitude of sequences that fold into a beta sheet of a specific length. This allows widely divergent sequences to converge on the same structure and form beta-sheets of identical size and orientation. As a result, very different sequences can converge on the same fold.

What drives the evolution then of the 1000 or so existing stable protein folds is not randomness, although random changes in the sequence help evolution get to these stable forms. The stable protein forms that exist are the natural and robust result of the order in the underlying physics and chemistry.

Now, one could argue that despite the order influencing the emergence of protein forms, sequences that give rise to these 1000 or so forms are still rare amongst all possible sequences. For example, if the are 10150 100 amino acid long sequences, it is possible that only 1080 fold into one of these limited array of stable structures. That would mean that only 1 in 1070 sequences would fold, which still would represent a significant hurdle for an evolutionary process. The empirical evidence though suggests that alpha helices and beta sheets have a propensity to form at a much higher frequency in random sequences, again due to the underlying order. While the exact number is hard to pin down, various studies suggest that the frequency by which stable structures form is between 1 in 102 and 1 in 1011.[4] This is a frequency that evolution can work with, but again it is a frequency that is dependent upon what Darwin called the “laws impressed upon matter.”




Kuebler, Dan. "The Amazing Natural Order Behind “Random” Protein Folding" N.p., 23 Feb. 2017. Web. 28 March 2017.


Kuebler, D. (2017, February 23). The Amazing Natural Order Behind “Random” Protein Folding
Retrieved March 28, 2017, from

References & Credits

[1] It is unfortunate that the term “intelligent design” has become the moniker for the ID movement given that it greatly restricts the traditional notion of intelligent design.  Most theistic evolutionists would agree that the universe has been intelligently designed in the traditional philosophical sense; i.e. the universe is ordered and owes its existence to God. The modern ID movement has taken the term and restricted its meaning in the public debate to a limited argument about the ability of natural processes to produce biological structures.

[2] Govindarajan, S., Recabarren, R. and Goldstein, RA. (1999) Estimating the total number of protein folds. Proteins: Structure, Function and Genetics 35:408-414.

[3] Denton, M.J., Dearden, P.K., Sowerby, S.J. (2003) Physical law not natural selection as the major determinant of biological complexity in the subcellular realm: new support for the pre-Darwinian conception of evolution by natural law. BioSystems 71:297-303.

[4] Dill, K. (1999) Polymer principles and protein folding. Protein Science 8; 1166-1180.

About the Author

Dr. Kuebler is a Professor of Biology at Franciscan University of Steubenville and teaches courses in evolutionary biology, cell biology, and human physiology. His biological research involves two major projects, 1) understanding the relationship between metabolism and seizure disorders and 2) examining the effects that various biologics have on human mesenchymal stem cells. In addition to his lab research, he is the co-author of The Evolution Controversy: A Survey of Competing Theories, a book that critically examines the various theories of evolutionary thought. He has also published a variety of popular articles on science, politics, culture and religion. He received a Ph.D. in Molecular and Cell Biology from the University of California, Berkeley and earned a Masters of Science in Cell and Molecular Biology from the Catholic University of America. He also holds a Bachelors degree in English from the Catholic University of America.


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