Basic molecular building blocks of the body, protein molecules are made up of hundreds of smaller molecules called amino acids. A particular protein molecule has its sequence of amino acids specified in DNA by a gene that is a sequence of nucleotide base pairs that stands for a series of amino acids (the building blocks of proteins). Certain combinations of these nucleotide base pairs (guanine, cytosine, adenine, and thymine) represent particular amino acids, under the coding system that is called the genetic code.
Now, based on what you have just been told, you might think that proteins are long string-like molecules like the long string-like molecule that is the DNA molecule. In other words, you might think that a protein looks like the chain we see in the visual below. A series of amino acids such as this, existing merely as a wire-like length, is sometimes called a polypeptide chain.
But protein molecules instead typically have intricate three-dimensional shapes. So a protein molecule isn't shaped like a simple length of copper wire. It looks more like some intricate copper wire sculpture that some artisan might make. Below is an example of one of the thousands of 3D shapes that protein molecules can take. There are countless different variations.
One of thousands of protein molecule shapes (Credit: RCSB Protein Data Bank)
Human DNA has about 20,000 different genes, each of which specifies a different type of protein molecule. Each protein molecule typically has a unique shape. Protein molecules need to have shapes like the shapes they have in order for them to function properly. A protein molecule will not do its job if it exists as a simple string-like object.
A fundamental question is: how do protein molecules get their three- dimensional shapes? This problem is known as the protein folding problem. We might have an answer for this if it happened that each amino acid stored in it three numbers specifying the 3D position that it should go to. We can imagine a setup in which an amino acid would store three different numbers: one representing the X-axis coordinate that the amino acid should exist at, another representing the Y-axis coordinate the amino acid should go to, and a third representing the Z-axis coordinate the amino acid should go to. We can imagine some complicated molecular machinery that would read such numbers, and drag each amino acids to the appropriate X, Y and Z coordinates (a particular point in 3D space) that the amino acid should go to. Under such a system, a 3D protein molecule like the one above might be constructed from a one-dimensional string-like chain of amino acids.
But that is not at all the way nature works. An amino acid does not store any numbers. An amino acid stores neither 3D coordinate numbers, nor any other type of number. So how do the more than 20,000 types of protein molecules in our bodies get their intricate 3D shapes?
Around the year I was born, the question was a profoundly troubling one for materialist biologists. It seemed around then that nature was making very many thousands of intricate hard-to-achieve 3D molecular shapes, and no one knew how it was happening. The materialist biologist was therefore like some owner of a private island who kept seeing endless varieties of intricate sand castles being constructed on the beaches of the island, without any explanation of who was doing it.
Eventually an idea arose that helped make materialist biologists feel much better. The idea was that the three-dimensional shape of each protein molecule was somehow determined by its one-dimensional sequence of amino acids. The idea was originally presented under the name of the Thermodynamic Hypothesis. The idea was that there was one particular 3D shape under which some polypeptide chain would use the least amount of free energy, and that polypeptide chains migrated to this state, which corresponded to their folded 3D shapes. This Thermodynamic Hypothesis was stated like this by Christian B. Anfinsen in 1973: "This hypothesis states that the three-dimensional structure of a native protein...is the one in which the Gibbs free energy of the whole system is lowest; that is the native conformation is determined by the totality of inter-atomic interactions and hence by the amino acid sequence, in a given environment." Later the same idea was called Anfinsen's Dogma, and was stated as simply the idea that the three-dimensional structure of a protein molecule is determined by its one-dimensional amino acid sequence.
Anfinsen's Dogma is represented by the visual below:
But Christian B. Anfinsen claimed to have done some experiments supporting his dogma. He did some experiments in which he took one of the simplest proteins (something called ribonuclease), and caused it to lose its folded shape, by a process called denaturation. Anfinsen claimed that he had observed ribonuclease revert back to its folded three-dimensional shape. He claimed that this was evidence that the three-dimensional shape of the protein was a mere function of the amino acid sequence. This was always weak evidence for a claim that protein molecules in general get their three-dimensional shapes solely as a consequence of their amino acid structure and the laws of chemistry and physics. One reason was that ribonuclease has only 124 amino acids, but most protein molecules have far more amino acids. The average number of amino acids in a human protein molecule is about 470, and many human protein molecules have much more than 500 amino acids (some having nearly 1000 amino acids).
Although his experimental evidence for Anfinsen's Dogma was weak, Anfinsen won the Nobel Prize in Chemistry in 1972, along with two other scientists, specifically for his experiments with ribonuclease. We should not be too impressed by this fact. We must remember that when scientists really, really want to believe something, they may tend to award some prize for experimental or observational activity that claimed to back up the cherished belief. The awarding of the Nobel Prize to Anfinsen and his colleagues was part of the social construction of the triumphal legend that Anfinsen's Dogma had been backed up by experimental work.
A 2012 paper has a statement suggesting that scientists were lazy about trying to produce some other experiments that would support Anfinsen's Dogma. It states this: "In the half-century since the annunciation of the Anfinsen postulate, there has appeared no evidence which contradicts it, but neither, seemingly, has there been any systematic experimental work on other proteins which would have further established its validity." We should not take the first half of that statement too seriously, because scientists often claim that is no evidence contradicting some beloved dogma, when there does exist very much such evidence.
A 2018 paper ("Modeling protein folding in vivo") suggests that the assumptions of Anfinsen were incorrect, and were derived from biased experiments dealing with a set of simpler-than-average proteins. The paper states the following, using the term "in vitro" to mean "in a lab setting," "native conformations" to refer to the 3D shapes of protein molecules, and "denatured" to refer to proteins that have lost their characteristic three-dimensional shape, and reverted to a simpler string-like or chain-like one-dimensional shape:
"These models arose from studies conducted in vitro on a biased sample of smaller, easier-to-isolate proteins, whose native structures appear to be thermodynamically stable. Meanwhile, the vast empirical data on the majority of larger proteins suggests that once these proteins are completely denatured in vitro, they cannot fold into native conformations without assistance. Moreover, they tend to lose their native conformations spontaneously and irreversibly in vitro, and therefore such conformations must be metastable."
Referring to "premature optimism," the paper discusses a kind of "rush to uncork champagne bottles" involved with the Anfinsen experiments:
"The most famous of these studies were the experiments by C. Anfinsen and colleagues, which observed that some small proteins, notably pancreatic ribonuclease (RNAse A), will fold spontaneously to their native conformations from an apparently completely denatured state after the restoration of favorable conditions in vitro; such an ability was postulated – in our opinion, with premature optimism – to be inherent to most proteins. These ideas gave rise to the 'thermodynamic hypothesis' stating that 'the three-dimensional structure of a native protein in its normal physiological milieu...is the one in which the Gibbs free energy of the whole system is the lowest' [17]. In other words, under physiological conditions all proteins were assumed to be able to fold spontaneously into their native conformation."
The paper states the following, using the term "in vitro" to mean "in a lab setting," "denatured" to refer to proteins that have lost their characteristic three-dimensional shape, and reverted to a simpler string-like or chain-like one-dimensional shape, and the term "native conformation" to refer to the three-dimensional shape that protein molecules have in living organisms:
"Simple and elegant as these models are, they fail to adequately accommodate some common empirical observations. The first one is the widely observed protein physical instability in vitro: most protein preparations that are initially isolated from cells in an active native conformation are not stable in vitro and inevitably denature and lose such native conformation (reviewed in [13,14,15,16]). The second is the body of experimental observations that even seemingly stable proteins, once experimentally denatured in vitro in isolation from other cell components, are often unable to fold back into their native conformations upon return to physiological conditions [29,30,31,32,33,34,35]. This phenomenon is observed for all classes of proteins, though it becomes more obvious and almost universal for proteins of larger sizes. It has been shown that many such proteins require the assistance of molecular chaperones for successful folding (reviewed in [36])...We are now witnessing the emergence of a third observation that casts doubt on the applicability of the thermodynamic folding model to the majority of proteins: despite the tremendous intellectual and computational efforts invested into modeling of protein folding in silico, software based on the current thermodynamic theory of folding is able to model the folding paths of only very short proteins, and the process is slow [41,42,43]. In other words, the model in which a polypeptide with a random starting conformation slides down the energy funnel towards the thermodynamic minimum, reducing its free energy at every step in the process, does not appear to yield successful in silico recapitulation of the folding pathways for the majority of proteins."
The limited success of the AlphaFold software (in attempts at protein folding prediction) does not invalidate any of the statements above. The AlphaFold software is able to predict the shape of many proteins not by any thermodynamic calculation process that tends to validate Anfinsen's Dogma, but instead by a frequentist "pattern matching" approach that relies on some vast database of known 3D protein shapes and their corresponding amino acid sequences. In discussions of the protein folding problem, it is very important to not mix up two very different problems:
(1) The protein folding problem, which is the problem of how it is that one-dimensional polypeptide sequences (chains of amino acids) very quickly within organisms fold into a three-dimensional shape needed for the function.
(2) The protein folding prediction problem, which is the problem of what computer techniques can be used to accurately predict the three-dimensional shape of a protein molecule, giving its one-dimensional polypeptide sequence.
The AlphaFold software has made progress on the second of these problems, not the first. News reports about the AlphaFold software will often inaccurately describe it as having made progress on the "protein folding problem" (the first of these problems), but such reports should be only reporting that progress has been made on the second of these problems (the protein folding prediction problem).
Later attempts to replicate Anfinsen's work with ribonuclease have raised grave doubts about how valid his research was. A very interesting paper published in the year 2022 was entitled "The Anfinsen Dogma: Intriguing Details Sixty-Five Years Later." In it a team of scientists reported many a problem in trying to replicate Anfinsen's work with ribonuclease. They seemed to get only a small fraction of the success that is generally claimed in accounts of Anfinsen's experiments.
Referring to what have been called metamorphic or "moonlighting" proteins which seem to be able to assume different 3D shapes, a paper states this about Anfinsen's "one sequence, one structure" dogma:
"Moreover, nuclear magnetic resonance spectroscopy
(NMR)-based and computational studies have demonstrated
that each protein sequence can have considerable structural plasticity, such that the 'one sequence, one structure' dogma
does not capture the complex nature of a protein’s structure. In
fact, this flexibility is an intrinsic feature that contributes
directly to the biological function of many proteins."
At the www.researchgate.net site (an "expert answers" site similar to Quora.com), there is a page handling the question "Are Anfinsen and Levinthal still considered valid in protein folding? The question is basically asking whether Anfinsen's Dogma is any kind of explanation for the biologically vital process of protein folding. A Michael Crabtree of Oxford University claims "Anfinsen's conclusion - that protein structures are encoded within their sequence - is still the main hypothesis for how proteins fold." Be suspicious when a scientist does not claim that something is proven, but merely claims that it is "well-established" or "not controversial," for scientists often use such phrases to describe dubious claims that are not actually well-established. And when a scientist does not claim that something is well-established, but merely says that it is the "main hypothesis" to explain something, that means very little, because his "main hypothesis" to explain something may be a very bad one. Crabtree's response is then vigorously disputed at length on the page by Boguslaw Stec PhD. He states this:
"As you see there are significant developments that no longer support a simplistic notion of sequence-folding-function direct relationship. The best proof is an entire career of Baker who is the most prominent protein modeler in the world now. He showed a complete failure of the energy based optimization schemes for protein modeling."
Stec makes this sobering observation:
"This is mostly in line with a sobering recent realization of NIH in the US that around 90% all biology science results are NOT repeatable. Scientist publish what worked not a majority of experiments that do not, even if this is the same experiment."
After describing at some length why Anfinsen's Dogma does not hold up well in experiments, Stec offers this idea as an alternative:
"It looks like life is tinkering on the edge between stable and unstable world. What it practically means is that proteins are self organized systems that do not have any uniform organizing principle. The only universal principle is a utilitarian need for life (function)."
Self-organization is a phrase that is routinely used by people lacking a theory of organization explaining how some very organized thing got organized. Stec makes it sound rather like proteins are little minds seeking out biological functions, but that cannot explain why sequences of amino acids (polypeptide chains) are able to form so very quickly into the correct three-dimensional shapes needed for biological function. Claiming self-organization in this case is no more credible than trying to explain the origin of well-written functional paragraphs by claiming that the letters self-organized into paragraphs.
Very much undermining Anfinsen's Dogma is the fact that a large fraction of all protein molecules require other protein molecules (called chaperones) in order for them to achieve their folded state. Such an idea discredits the simplistic "amino acid sequence determines 3D folded shape" idea. A Stanford University press release states this:
"Scientists have determined that TRiC chaperones are common in people and other mammals. Estimates are that 10 percent of all mammalian proteins need TRiC in order to fold properly. Another 20 percent bind to the smaller chaperone, Hsp70."
That already give you 30% of protein molecules requiring other protein molecules for them to fold properly, undermining Anfinsen's idea that all you need is the amino acid sequence to get the proper folding for a protein molecule. An encyclopedia page concurs, stating that "20 to 30 percent of polypeptide chains require the assistance of a chaperone for correct folding under normal growth conditions."
Further evidence against Anfinsen's Dogma comes in the fact that a large fraction of all human proteins are what are called "Intrinsically Disordered Proteins," a poor name for a large class of proteins that can each assume many different shapes. A much better name would be "shape-shifting proteins" or "morphologically plastic proteins." Besides such shape-shifting proteins (called IDPs), a protein with a characteristic 3D shape may have some particular part of itself that takes on different shapes, such a part being called an "Intrinsically Disordered Protein Region or IDPR." A rough analogy of proteins with such IDPRs might be a person with a magically shape-shifting face, who always looks the same below the neck, but whose face can shift between different faces. It has been estimated that up to 40% of human proteins are either either such shape-shifting proteins (IDPs) or proteins that have shape-shifting regions (IDPRs). A scientific paper tells us this about such IDPs and IDPRs:
"IDPs/IDPRs, which are characterized by remarkable conformational flexibility and structural plasticity, break multiple rules established over the years to explain structure, folding, and functionality of well-folded proteins with unique structures. Despite the general belief that unique biological functions of proteins require unique 3D-structures (which dominated protein science for more than a century), structure-less IDPs/IDPRs are functional, being able to engage in biological activities and perform impossible tricks that are highly unlikely for ordered proteins. With their exceptional spatio-temporal heterogeneity and high conformational flexibility, IDPs/IDPRs represent complex systems that act at the edge of chaos and are specifically tunable by various means....Overall, IDPs/IDPRs are complex systems with sophisticated structurally and functionally heterogeneous organization. They are uniquely placed at the core of the structure-function continuum concept, where instead of the classical (but heavily oversimplified) 'one gene–one protein–one structure–one function” view, the actual protein structure-function relationship is described by the more convoluted 'one-gene–many-proteins–many-functions' model [92, 93]."
What we have in the case of Anfinsen's Dogma is an example of what has repeatedly occurred in the history of modern biology: the social construction of a dubious achievement legend, one hoisted up triumphantly largely for ideological reasons, so that biologists could claim they understood some great mystery of nature they did not at all understand, and could avoid believing in something they did not want to believe in. It works like this:
(1) Biologists will make observations of some type of extremely impressive phenomenon in nature, or some class of phenomena.
(2) One or more biologists will come up with some simplistic half-baked hypothesis that purports to offer a naturalistic mechanistic explanation for the phenomenon or class of phenomena. Typically such a hypothesis is stated through the repetition of some "sound bite," slogan or catchphrase such as "energy minimization," "natural selection," or "synapse strengthening."
(3) It will be claimed that a few miscellaneous observations or experiments lend support to the hypothesis.
(4) Limitations or defects of the observations or experiments will be ignored, and a grand chorus of biologists will start proclaiming in unison that the hypothesis is a suitable explanation for the phenomenon or class of phenomena.
(5) Gigantic reasons for rejecting the hypothesis will be ignored or swept under the rug.
(6) Illogical aspects of the hypothesis (or aspects contrary to facts) will be ignored or swept under the rug.
(7) A triumphal legend will be socially constructed by the biologist community that the impressive phenomenon or class of phenomena has been explained, because of the hypothesis offered, and the weak cheesy evidence presented in favor of it.
This is exactly what happened in the case of Darwinism, which never offered a credible explanation for the more impressive wonders of biological innovation occurring in natural history, merely offering the cheesy sound-bite slogan of "natural selection" and an implausible appeal to random mutations. This is also what happened in the case of the main phenomena of the human mind, none of which are credibly explained by brain activity, for reasons I explain at great length in the posts of the blog here.
Do not be fooled by claims that Levinthal's Paradox or the protein folding problem has been solved. Such claims are merely additional examples of the countless times scientists have made triumphant declarations that they solved problems they did not actually solve. Each claim that Levinthal's Paradox or the protein folding problem has been solved typically involves appeals to dubious speculative physics, appeals that have not been substantiated by experiments. The different claims of this type all disagree with each other, each presenting a different speculative framework. Claims that Levinthal's Paradox or the protein folding problem has been solved are as dubious and speculative as when some scientist claims to have solved the origin of life, the origin of consciousness or the puzzle of what could have caused the origin of the universe.
A scientific paper states this, using "native conformation" to mean the characteristic 3D shape of a protein molecule:
"The problem of protein folding is one of the most important problems of molecular biology. A central problem (the so called Levinthal's paradox) is that the protein is first synthesized as a linear molecule that must reach its native conformation in a short time (on the order of seconds or less). The protein can only perform its functions in this (often single) conformation. The problem, however, is that the number of possible conformational states is exponentially large for a long protein molecule. Despite almost 30 years of attempts to resolve this paradox, a solution has not yet been found. A number of authors (see, e.g., Ben-Naim, 2013; Onuchic and Wolynes, 2004; Finkelstein et al., 2017) believe that there is a solution, but they disagree on the reasons. Other scientists (see, e.g., Berger and Leighton, 1998; Davies, 2004) believe that the paradox is not yet resolved."
The phenomenon of protein folding is one of the most important things that goes on in nature, and your biological persistence from day to day vitally depends on protein folding occurring each day. Most protein molecules are short-lived. For example, the proteins in brain synapses have an average life of less than two weeks. Your body requires for protein folding to continuously occur, so that short-lived protein molecules can be continually replaced by newly created protein molecules that almost all require just-the-right protein folding to work right. The paper "Systematic study of the dynamics and half-lives of newly synthesized proteins in human cells" tells us this: "The majority of the proteins quantified have half-lives within the range of 4–14 hours. About 6% of all quantified proteins (49) have half-lives <4 hours, while 51 proteins have long half-lives (>14 hours); the median half-life is 8.7 hours."
The fact that Anfinsen's Dogma is not a credible or well-established explanation for protein folding (and the fact there is no credible mechanistic explanation for protein folding) is a fact of the utmost philosophical importance. If the daily protein folding that occurs in your body is a marvel of organization very far beyond the explanatory capabilities of mechanistic science, then we should suspect a gigantic reality totally contrary to the dogmas of mechanistic materialism: that your continued existence is continually dependent on some purposeful unfathomable agency that cannot be explained by mere physics or chemistry. Properly understanding the protein folding problem and the failures of attempts to explain it are one of quite a few factors that give rise to a doctrine that is the polar opposite of reductionist dogmatism: the doctrine of continuous life-force dependency explained here.
The unsolved mystery of protein folding is related to the unsolved mystery of morphogenesis and human development, the problem of how a speck-sized zygote is able to progress to become the vastly more organized state of a human body. Just as biologists had some very cheesy and dubious phrases to mutter to try to sweep the gigantic problem of protein folding under the rug (phrases such as "Anfinsen's Dogma" and "the amino acid sequence determines the final structure of the protein molecule") -- a problem they failed to solve in any credible way -- biologists had a not-actually-true phrase to mutter when people asked about morphogenesis: the claim that human structure arises because a DNA blueprint is read. Such a claim was always a phony childish tale. DNA does not specify any blueprint of human anatomy. DNA merely specifies low-level chemical information such as which amino acids make up a protein. And even if DNA had a blueprint for building humans, it would not explain the origin of an adult body, because blueprints don't build things. Things get built with the help of blueprints because purposeful agents such as construction workers get ideas about how to build thing using blueprints.
The shocking truth (so immensely contrary to the triumphal boasts of biologists) is that biologists understand neither the origin nor the continuation of any adult human body, as the conversation below explains:
Jack: What did you say, that we don't understand how an adult body originates? Of course we understand that! Your body originated because your mother got pregnant, and your body grew in your mother's womb.
Jill: How a mother gets pregnant is the simplest thing: just a uniting of a sperm and egg. But we don't understand how the next nine months occur. How does some fantastically organized human body -- with an arrangement of parts more impressive than in a jet fighter -- arise from the speck-sized simplicity of a newly fertilized egg, a zygote? We don't understand that.
Jack: It's simple. There's a blueprint for making a body in your DNA, and the body reads that, and carries out its instructions.
Jill: That's a fairy tale. There is no such blueprint in DNA. DNA just has low-level chemical information, such as which amino acids make up a protein molecule. DNA does not even specify how to make any of the 200 types of cells in our bodies, each a marvel of functional organization. We don't understand how adult bodies originate, and don't even understand how they continue to exist once they've appeared.
Jack: What are you talking about? I continue to exist because I keep breathing air, keep eating food, and keep drinking water. So that fuels my heart so it keeps beating, and my lungs so that they keep breathing.
Jill: Yes, you need all that. But you need a lot more. You need for your body every day to do protein folding. Strings of hundreds of amino acids, kind of like a long necklace of tiny beads, must always be folding in just the right way to make these elaborate 3D protein shapes that your body needs. Without that, you'd be dead in a few weeks. How does protein folding happen? It's a miracle of origination a thousand miles over our heads, like a thousand types of sand castles arising on a beach when there's no one there.
The Anfinsen story is a classic example of folly in modern science. A scientist (Anfinsen) did an experiment with a very small molecule (less than one third the average size of a human protein), and claimed that this showed that the 3D structure of most proteins is determined solely by their amino acid sequence (Anfinsen's Dogma, also called the thermodynamic hypothesis). This was rather like a man claiming that he built a house, and claiming that this shows that a single man can build an entire cathedral. Because scientists were eager to embrace the mechanistic dogma that protein shapes are determined solely by amino acid sequences, a Nobel Prize was soon awarded to Anfinsen, and innumerable science books and articles started claiming that his work proved his dogma (even though it made no sense to make such a claim based on Anfinsen's meager experimental results involving so small a molecule). There was little work done to try to do further experiments that might verify Anfinsen's claims, such as trying tests like his with average-sized proteins. Scientists had their triumphal story, and did not want to do further tests that might spoil that story. After fifty years of the science literature making the groundless claim that Anfinsen's experiments had proven his dogma, some diligent scientists finally tried in their 2022 paper to replicate his experiments, and found they could not even replicate them. So it was fifty years of science literature misinforming us on this important topic of whether the 3D structure of protein molecules is determined by their amino acid sequence, stretching right up to the present Nobel Prize announcement. The failure to replicate Anfinsen's results has been largely ignored, and the misleading claim about Anfinsen keeps being repeated.
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