The mystery of protein folding: Nobel laureate summarizes his insights into the physical backgrounds

Aug 14, 2012
The mystery of protein folding: Nobel laureate summarizes his insights into the physical backgrounds

Living subjects are very complex systems and, at the same time, stunningly robust and accommodative. The secret of success are their proteins which build up the cells of the organisms, act as cleaners, messengers, transporter, motors, and fulfill much more jobs. How proteins are genetically coded and how their linear chains of amino acids are put together, is in principle well known. Yet, this is not the full story. Before proteins can do their jobs, they have to be folded in a proper way. This is important because the shape determines the function of the protein. And misfolded proteins can cause severe health disorders, such as Morbus Alzheimer. The cause seems to be that they tend to aggregate into so called amyloid plaques.

It is still impossible to predict from the how the corresponding protein will fold. New insights into the principles or protein folding could enhance the understanding of amyloid based diseases. In addition, could be custom tailored for special target molecules.

Ahmed H. Zewail and his co-worker Milo M. Lin summarize their insights into the physical backgrounds of protein folding in the latest issue of Annalen der Physik as part of the renowned Einstein Lectures. This series, established in 2005 in the course of the Einstein Year, comprises articles of reputable scientists such as Nobel laureates Theodor Hänsch, Roy Glauber and Peter Grünberg. Now, Zewail and Lin report about physical views of protein folding.

Many proteins are able to fold themselves quickly and properly into a complicated conformation without any help of a cellular “folding apparatus”. How they achieve this is still a mystery. Zewail and Lin at the California Institute of Technology in Pasadena (USA) want to solve this “protein folding problem“ by looking at the basic physics behind the complex world of proteins.

Besides thermodynamics which control the stability of the possible protein conformers, kinetic aspects play a key role as they rule the mechanisms and time scales of the folding process. A polypeptide chain could spend more time than the age of the universe “trying” all of its possible conformers to find its native one. In reality, folding never takes more than a few seconds.

Using ultrashort laser pulses, Zewail’s team was able to determine how fast the first twist of an alpha-helix is formed. Real-time investigation of chemical reactions with ultrashort laser pulses is one of Zewail’s specialities; his research in this area had been acknowledged with the donation of the Nobel prize in 1999.

The folding of the first helix twist is the fastest step of ; it therefore determins the general speed limit of folding velocity. Without having to know the details of all mechanisms involved, the scientists were able to calculate this general limit with the help of simple analytical models.

The models used are based on a consideration of the torsion angles in the backbone plotted in a so called Ramachandran diagram. Sterically forbidden, restricted and free regions are distinguished. In addition, the polypeptide chain was calculated as a three-dimensional lattice thereby arranging the chain in a way that maximizes contacts between hydrophobic residues reflecting their shielding from the physiological aqueous environment. The polar sidegroups, instead, have to point outwards. This corresponds to the natural conformation of proteins.

Based on their calculations, Zewail and his colleague argue that hydrophobic interactions between non-polar amino acid residues are sufficient to fold a polypeptide chain into its native shape in a reasonable time. But this works only if the chain is not longer than ca. 200 amino acids. This could be an explanation for the observation that proteins are built up of domains: Although proteins, in general, may consist of more than 1000 amino acids, they are often composed of domains of independently folding sub-parts. These domains are on average 100 long, most of them being less than 200. This would correspond to the theoretically determined length regime for which hydrophobic interactions are sufficient for fast folding.

Explore further: New method to analyse how cancer cells die

More information: Lin, M. M.; Zewail, A. H.: Ann. Phys. (Berlin) 524(8), 379-391 (2012)
In this issue: Ann. Phys. (Berlin), Vol.524, No. 8 (2012) onlinelibrary.wiley.com/doi/10.1002/andp.v524.8/issuetoc

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kevinrtrs
1 / 5 (12) Aug 14, 2012
Proteins are the bane of the idea of spontaneous emergence of life as we know it.
In order to make proteins you need the machinery to decode, copy and then construct the protein. BUT - the machinery itself is made up of proteins and needs the information from another protein.
Which came first, the protein or the protein?
As for the folding of said proteins, where do the chaperones come from in the first place - no proteins, no chaperones. No chaperones, no proteins. Enough to drive the evolutionist who believes in spontaneous eruption of life to the brink.
ValeriaT
5 / 5 (5) Aug 14, 2012
In order to make proteins you need the machinery to decode, copy and then construct the protein
Of course not, proteins are polymers of aminoacids and they form spontaneously. In the 1950s and 1960s, Sidney W. Fox studied the spontaneous formation of peptide structures under conditions that might plausibly have existed early in Earth's history. He demonstrated that amino acids could spontaneously form small peptides. These amino acids and small peptides could be encouraged to form closed spherical membranes, called proteinoid microspheres, which show many of the basic characteristics of 'life'. And aminoacids are known to be formed spontaneously too (Miller-Urey experiment 1953).
Deathclock
4.2 / 5 (5) Aug 14, 2012
Perfect example of someone who has no idea what they are talking about put in their place by someone who knows exactly what they are talking about...
aroc91
5 / 5 (3) Aug 14, 2012
Do your job, moderators. You're still willfully ignoring kevin's religious trolling.
Torbjorn_Larsson_OM
4 / 5 (4) Aug 14, 2012
Creationists shouldn't comment on science, it is hilarious to see.

I knew protein folding was a creationist troll bait, but I didn't think they would have opted to forgo "spontaneous folding, therefore gods" for a "chicken and egg, therefore gods" argument. That is even stupider, because it is precisely "chicken-and-egg" interlocking systems that are predicted by evolution. [Muller, ~ 1930.] I.e. you can't take away a mouth when you have evolved a lung function by small, survivable changes.

Creationist random "poofing" out of nothing (no mechanism) explains nothing of that, their non-constrained magic idea could produce animals with any number of legs for example.
Torbjorn_Larsson_OM
3 / 5 (2) Aug 14, 2012
[cont] Here it is known, and I know this troll has read it but won't respond, that the RNA world was an ancestor to the DNA LUCA. RNA is the core of the genetic system.

And consistent with that it is observed by modern complete genome methods that protein fold family phylogenies and proxy clocks maps to a DNA LUCA of a 20 % period on the proxy clock, before the modern domain diversification, and an RNA/protein world of another 20 % before that. ["The evolution and functional repertoire of translation proteins following the origin of life", Goldman et al, Biol Dir 2010.]

So protein folds, that folds spontaneously, was recruited one at a time as soon as the RNA world have started to utilize and code for longer amino acid heteromers. Before that they were useful as other coenzymes are today, aa chains with 1-2 mers can act as catalytic center.
Torbjorn_Larsson_OM
3 / 5 (2) Aug 14, 2012
[cont] But now we get into astrobiology, so I feel motivated to delve into the process from chemical to biological evolution:

Of course the spontaneous folding exist in RNA as well, it is how they form ribozymes and self-interacting ribozymes at that. But that is much simpler folds. and did not require co-enzymatic functionality as such to tide the chemical evolution over. Rather, energetically activated nucleotide mono- and dimers made later energy carriers such as ATP et cetera.

RNA heteromers are produced spontaneously after nucleotides are energetically activated. That can happen on terrestrials by naturally occurring polyphosphates produced around subduction zones of plate tectonics and released in hydrothermal vents in such areas.
Torbjorn_Larsson_OM
3 / 5 (2) Aug 14, 2012
[cont] And RNA heteromers are selected because under anoxic and iron filled conditions of early Earth they were prodigious catalysts.

Catalysts enhanced the productivity of naturally evolving metabolic networks by making them sparse and focused as modern metabolism, and the successful networks produced their own catalysts resulting in exponential feedback. This is enough to show that the necessary gradualism (evolution by small steps) and driving forces (selection on variation) were in play.
Torbjorn_Larsson_OM
3 / 5 (2) Aug 14, 2012
[cont] Ironically in this perspective, in comparison with Mars Earth is the rusty planet, but the rust goes deeper.

Life got started because the oxidation end of redox cycles out of geothermal and solar irradiation energy made methane faster out of CO2 and H2O when catalysts and later cellular enzymes opened up the energy channel where free energy could fastest dissipate. Chemical evolution is the way nature attacks more volatiles.

But the redox chain ends with oxidizers attacking crust. Counterintuitively the free oxygen in the atmosphere is claimed to stand for only 1-2 % of the reduction, sulfur still stands for ~ 25 % and ~ 75 % is iron which oxides then gets reworked in our much more geothermally active mantle. Biological evolution is the way nature makes more rust.

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