The basic premise of protein folding

A molecule is a set of atoms connected to each other by covalent bonds. A covalent bond involves the sharing of an electron pair across two nuclei.  When two atoms are so bonded, their movements relative to each other become very restricted in all degrees of freedom, translational and rotational, except one - rotation on the axis of the bond. Within the domain of temperatures viable to life on Earth, single-bonded atom pairs freely rotate on the bond (though certain angles will be energetically favored over others and may even be forbidden by steric constraints in particular instances).

Polypeptides emerge from the ribosome in an alpha-helix form, effectively a straight rod. The polypeptide then spontaneously folds into its mature form almost exclusively by rotation on the two single bonds internal to each amino acid. All amino acids involved in protein synthesis have a central carbon (CA) with a single bond to a nitrogen (N) and another single bond to another carbon (C) that is itself double bonded to an oxygen (O). When two amino acids are joined by the ribosome, a bond is formed between the C of one and the N of the next. No rotation is seen on this new bond, however, because of the nature of oxygen and nitrogen. Nitrogen has a weaker hold on its electrons than does carbon whereas oxygen has a stronger hold. The result is that an other electron pair is drawn to some degree across the bond between the amino acids preventing rotation on that peptide bond.

The central carbon (CA) of all amino acid species except glycine also single bonds to a third carbon (CB) that further bonds to other atoms depending on the particular amino acid species involved. This so called side chain ( as opposed to the N-CA-C "backbone") must interact with the alpha-helix to direct the folding process since polypeptides differing only in the particular sequence of amino acid types are seen to fold in various but deterministic ways.
 

More on Ferritin

About 2.4 billion years ago the Great Oxygenation Event began and, for the next 600 million years, oxygen from photosynthetic blue-green algae entered the oceans and the atmosphere. Life on Earth then had to adapt to the then poisonous effects of free oxygen.  Some organisms persisted even to this day in compartments where oxygen does not reach. Others had to evolve to withstand and eventually to exploit the new conditions.

One problematic condition facing life was the disappearance of soluble iron as the soluble ferrous form was driven to the insoluble ferric form as oxygen entered the oceans. Iron then precipitated out and formed the banded iron formations that supply much of modern iron ores. Iron, which before was plentiful, suddenly became scarce and, even to this day, algae cannot thrive in the central oceans for lack of it. Near shore where iron is available from land runoff and from cycling of shallow sediments photosynthetic life persisted, principally by evolving the protein ferritin so that iron could be stored in a compact mineral form in the cell. 24 ferritin molecules interact to form a hollow sphere into which ferritin precipitates iron atoms by reversibly removing an electron to form the ferric form from the soluble ferrous form. A single sphere can then store up to 4500 iron atoms. So successful was this approach that ferritin has remained structurally identical in nearly every organism on Earth for 2 billion years.

These filled ferritin spheres are ferromagnetic and could then have served as the basis for sensors of the Earth's magnetic field. Also because of their density they could serve as the basis for sensors of gravity and motion as well. Perhaps, thanks to ferritin, cells could then evolve to sense their macro environment.  Motile cells could then move with deliberation and animal life could become possible.

Ferritin

Iron is the most abundant element on Earth by mass. Super-massive stars are able to fuse elements to higher and higher atomic weights as they evolve. They then die in supernova explosions and spew out their fusion products.  It happens that fusion up to the atomic weight of iron is heat generating but then heat absorbing after that, so it is not surprising that so much iron has accumulated in the universe. Iron is a transition element meaning that it has unfilled lower orbitals in its neutral state.  It can thus accept or surrender electrons with little change in its free energy which makes it ideal for mediating chemical reactions. It also makes it dangerous as it can readily react to whatever it bumps into.  Life, therefore from the very beginning has had to deal with it and the simple protein ferritin has been a universal answer, at least for the storage aspect. All life forms, prokaryotes, eukaryotes, and archaea have variants of ferritin.  Mitochondria and plastids even have their own variants.  The structure of all variants is highly conserved. 24 ferritin molecules interact to form a hollow ball. Iron ions in the +2 ferrous form are then deposited by ferritin inside the shell in the +3 ferric form (up to 4500 atoms per shell!), available for withdrawal as the need arises.

I have chosen ferritin as the ideal target of my folding software for several reasons.  It is relatively simple consisting of just four alpha helixes with a strap between them, and the many variants all have basically the same structure.  Hundreds of x-ray crystallization studies have been done on its many variants to high resolution including waters of hydration. Finally it interacts with  itself to form predictable macro structures. Mutant forms have even been generated and crystallized to provide insights on its folding and aggregation dynamics. It does, however, lack beta sheets so I will have to find another target eventually to fool around with.

New Title!

For the last few years, apart from minor revisions to the Protein Cycling Diet book, I have been playing around with the question of predicting how a polypeptide would fold if you knew only its amino acid sequence. This question is the holy grail of protein chemistry and has proven to be an exceedingly difficult problem and I hardly expect to solve it. I am now approaching it with a tool that I have not found others to have yet employed namely Jmol, an interactive viewer for three-dimensional chemical structures and a brilliant piece of work currently maintained by Bob Hanson of St. Olafs university.

I used to do my folding work in Java and then use Jmol to display the results. After Bob added the ability to edit polypeptides and in particular to rotate bonds, I was able to do all my work with the Jmol scripting language.  My initial output was a library of Jmol scripts: a set of tools for generating and manipulating polypeptides (and polynucleotides) found here. Now I am attempting to write scripts for predictive folding and have decided to discuss my project in this blog. Accordingly I have changed the title to the more general topic, Protein folding. After all, the earlier diet topic was about how to help dispose of misfolded proteins, so I have only broadened the scope of the blog and will continue to speculate here on relevant developments in autophagy science as well.

New revision!

A new revision of the book is available in the links on the left.  I added chapters on anti-oxidants, cancer, cardiovascular diseases and supplements in view of recent studies, especially on the potential for protein cycling to benefit cardiovascular outcomes. The WordPress editor is a real bear and I've yet to figure out how to make a link to the middle of a page.  Instead I directed the footnotes directly to their sources and have updated the links to PDFs where available.

Update

Recent work has implicated autophagy in lipid processing and the cardiovascular community is buzzing with new studies on autophagy and heart disease.  For me personally heart disease, given my family history, is more likely to kill me than any neurodegenerative disease and so, I will look into the subject and add cardio-vascular diseases to the list of diseases that protein cycling might prevent.  There is a lot of literature to digest and this may take some time.

Update

Interesting new paper coming out soon in the journal Autophagy where extensive autophagy is observed in mouse neuronal tissue after only 24 hours of starvation. The authors even suggest that intermittent fasting would be therapeutic in view of their results. I'll jump the gun and add the pre-pub reference to the online book. While I'm at it, I'll fix a few typos too...