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Current Dogma as the Antithesis to Chaos and Complexity

The current dogma regarding the genetic code represents the antithesis to the concepts and foundations of chaos and complexity theories. The idea that proteins actually fold in a simple and linear fashion, as described by current dogma, should be an outrageous proposition to those who understand complexity. Let’s briefly outline the accepted theory:

1. Genetic information is stored in sequences of nucleotides.

2. The genetic code translates all of this information only into sequences of amino acids.

3. The sequence of amino acids alone determines the shape of a folded protein.

The lynchpin of this scenario is called the thermodynamic hypothesis of protein folding. This hypothesis holds that for any sequence of amino acids there is a single folded conformation that represents a global free energy minimum relative to all possible conformations of that sequence, and that it will be found in all cases of physiologic folding. Therefore, the universe has predetermined one native form for every possible sequence before the process of folding begins.

If this were true, we should expect to see a single conformation for any protein, independent of its nucleotide sequence or folding history. Indeed, early studies of denatured and refolded proteins seemed to support this hypothesis, but they have misled us. Translation has already ocurred, and denaturing a protein does not reverse the informative processes of translation. Confirmation of this acccepted hypothesis is still conspicuously absent. A rigorous proof should at least require prospective studies of folding a single primary sequence from multiple synonymous sequences. This proof is missing from the literature, and in fact contradictory evidence is available. Silent mutations do affect protein folding. In addition to this, curiously, codon usage is correlated with secondary structure.

The issue is actually much simpler than it has been made out to be. Given a sequence of amino acids, how many ways might we expect it to fold? If the answer is one, then we can continue to happily pursue the tenets of existing dogma. If a protein might fold many ways, then we must abandon the failed dogma before it does more harm - and it is doing considerable harm.

This is where chaos and complexity should rise up and be heard, because protein folding will be properly understood within that context. The process of folding a protein is complex, and it is sensitive to initial conditions. It is much more like the weather, or like an economy than it is like a ball on an inclined plane. We can easily come up with a long list of conditions that certainly divert a protein from folding along its ‘unalterable path of thermodynamic destiny.’ The most crucial of these conditions will involve the molecular apparatus of sequence translation, which is the heart of the genetic code.

Here is a metaphor to make the point. Consider a river that represents a single sequence of amino acids. One side of the river stands for all synonymous sequences of nucleotides that translate into those amino acids, and the other side of the river stands for all possible folded conformations of that sequence. The genetic code is a bridge between the two sides of the river.

Our current paradigm is the simplest one possible: All roads lead to one destination. But this view completely ignores the engineering of the bridge. Each crossing of the river has a timeline and a terrain. Each sequence is built in real-time with a diversity of components, and surely this alone leads to the probability of multiple destinations. This does not mean that every point on the nucleotide side leads to a distinct conformation, just that there are multiple potential destinations. Even if there are only a few, the fact that sequence does not inevitably lead to structure means that we are ignoring a vital part of translation. Genetic information defines the destination, and the genetic code gets us there.

This is more than just a metaphor; it tracks with reality. The genetic code lays down a physical bridge between nucleotides and protein conformations that is built in sections of tRNA. For every point of departure we must imagine the timeline and the physical contour of the bridge built by the genetic code. The sequence of amino acids lies not on codons but on a sequence of tRNA. The shape and state of initial conditions for every polypeptide as it enters the process of folding is directly determined by the sequence of tRNA, not codons. This is a non-trivial, informative physical reality with the very real opportunity to impact the path of a protein as it undergoes complex folds. These molecular scaffoldings in time and space represent genetic information at that point in the process. It is a system predicated on the non-linear outcomes from complex dynamics of protein folding.

If this translation is in reality a very simple process, then current dogma will prevail. If the process of folding a protein is complex and chaotic, like the weather, then initial conditions will be all important and our view of the genetic code must then be expanded.

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Last updated September 20, 2003 11:20 AM