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Two Views on the Protein Folding Puzzle

By: , Posted on: June 3, 2016

Protein chain folding is a miracle.

As seen in the figure below, the protein chain is gene-encoded and initially has no structure (below left) and its intricate structure (below right), with every atom in its unique position, results from spontaneous folding.

This is as amazing as if a multicolored thread could produce a shirt itself!

Fig. 1. Interconversion of two stable states of the protein chain via an unstable semi-folded intermediate. The colored helix, strands (strips) and loops (bold lines) show the chain fixed in the folded (right) or semi-folded (middle) structures; the globules are dotted. The broken line shows the structureless chain (left) and unfolded parts of the intermediate. The chain links (color beads) are gene-encoded. The most unstable semi-folded state acts as the free-energy barrier at the folding and unfolding pathways. Instability of the folding intermediatas, which is typical of proteins, results from the additional (by natural or artificial selection) reinforcement of the folded structures.
Fig. 1. Interconversion of two stable states of the protein chain via an unstable semi-folded intermediate. The colored helix, strands (strips) and loops (bold lines) show the chain fixed in the folded (right) or semi-folded (middle) structures; the globules are dotted. The broken line shows the structureless chain (left) and unfolded parts of the intermediate. The chain links (color beads) are gene-encoded. The most unstable semi-folded state acts as the free-energy barrier at the folding and unfolding pathways. Instability of the folding intermediatas, which is typical of proteins, results from the additional (by natural or artificial selection) reinforcement of the folded structures.

The chain spontaneously finds its stable fold (Figure 1: from left to right) within minutes or faster (both in vitro and in living cells), though much more than the entire life-span of the Universe would have been required to sample all possible chain structures in search for the most stable one. This is called “the Levinthal’s paradox”. To resolve it, various models of folding were proposed during decades.

However, these models fail to overcome the Levinthal’s paradox when the globular structure stability is close to that of the unfolded chain and provide for no estimate of the folding rates (spaning over 11 orders of magnitude, Figure 2).

The folding rate problem was solved using unfolding (not folding!) as the starting point, i.e., when the free-energy barrier between the globular and unfolded state (Figure 1, middle) was viewed “from the globule side” (Figure 1: from right to left).

The trick is that, firstly, the rates of the forward and reverse reactions coincide when the globular structure stability equals to that of the unfolded chain (according to the “principle of detailed balance” well-known in physics). Secondly, it is much easier to imagine – and investigate – how the thread unfolds than how it obtains a certain fold.

The validity of this theory (proposed two decades ago, when the experimental data were scarce) has been recently confirmed by all currently available experimental data (Figure 2).

However, dissatisfaction felt because the folding problem has not been solved yet “from the viewpoint of the folding chain” (Figure 1: from left to right) underlay further efforts made to estimate a volume of the necessary sampling in search for the most stable chain fold.

Recently, it has been shown that this volume, when considered at the level of formation and packing of the most strongly interacting protein structure elements (helices and strands, Figure 1) is by many orders of magnitude smaller than at the Levintal-considered level of separate chain links (beads in Figure 1), and the rate of its sampling, at folding, become physically and biologically reasonable (and close to the unfolding-derived estimates, Figure 2).

Fig. 2. Folding rates (circles and squares) of proteins, experimentally studied at equal stability of their folded and unfolded states. Yellow triangle shows the predicted (from consideration of unfolding!) range of these rates. The netted shading shows a recent theoretical estimate of the minimal rate of exhaustive sampling, at folding, of all possible packings of the protein secondary elements (helices and strands). The upper limit of the “Levinthal’s sampling time” is shown by the double dashed line.
Fig. 2. Folding rates (circles and squares) of proteins, experimentally studied at equal stability of their folded and unfolded states. Yellow triangle shows the predicted (from consideration of unfolding!) range of these rates. The netted shading shows a recent theoretical estimate of the minimal rate of exhaustive sampling, at folding, of all possible packings of the protein secondary elements (helices and strands). The upper limit of the “Levinthal’s sampling time” is shown by the double dashed line.

Thus, the protein folding puzzle is solved by viewing on it from two sides: the side of unfolding and the side of folding.

protein physics

Protein Physics: A Course of Lectures covers the most general problems of protein structure, folding and function; it describes key experimental facts and introduces concepts and theories. It deals with fibrous, membrane and especially water-soluble globular proteins, in both their native and denatured states. The book summarizes and presents in a systematic way the results of several decades of worldwide fundamental research on protein physics, structure and folding. It describes many simple physical models aimed to help a reader to estimate and predict of physical processes occurring in and with proteins.

The author, Alexei V. Finkelstein, has been invited to speak at the 4th International Conference on Integrative Biology on July 18-20, 2016 in Berlin, Germany. The book, Protein Physics: A Course of Lectures is scheduled to publish in July. If you would like to pre-order a copy at 15% off the list price, visit the Elsevier Store today. The author, Alexei V. Finkelstein, will be speaking at the 4th International Conference on Integrative Biology on July 18-20, 2016 in Berlin, Germany.

References
[1] Stages in the Mechanism of Self-organization of Protein Molecules. Ptitsyn O. B. Dokl. Akad. Nauk SSSR 1973, 210, 1213-1215.
[2] Rate of Protein Folding Near the Point of Thermodynamic Equilibrium between the Coil and the Most Stable Chain Fold. A. V. Finkelstein, A. Ya. Badretdinov Fold. Des. 1997, 2, 115-121.
[3] Golden Triangle for Folding Rates of Globular Proteins. Garbuzynskiy S. O., Ivankov D. N., Bogatyreva N. S., Finkelstein A. V. Proc. Natl. Acad. Sci. USA 2013, 110, 147-150.
[4] Reduction of the Search Space for the Folding of Proteins at the Level of Formation and Assembly of Secondary Structures: A New View on Solution of Levinthal’s Paradox. Finkelstein A.V., Garbuzynskiy S.O. ChemPhysChem, 2015 Sep 1

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