Folding the ferritin alpha helix

A polypeptide emerges from the ribosome as an alpha helix held in such configuration by hydrogen bonds (hbonds) between the backbone nitrogen of each amino acid and the backbone oxygen of the amino acid four positions away (cward, toward the C terminus of the polypeptide). Folding as a molecular process is likely orders of magnitude faster than polypeptide synthesis and occurs as soon as the opportunity arises as the alpha helix emerges from the ribosome.

In order to fold, that is to rotate on the bonds between the CA atom and the N (the phi bond) or C atom (the psi bond), hbonds must be broken. Specifically four hbonds in a row must be broken, allowing rotation on the psi and phi bonds as the helix unwinds until collisions or new hbond formation stops the rotation. Since the specificity of the side-chains determine the folding pattern, the side chains must be involved. From my observations, the following amino acids have side-chains that appear to disrupt alpha helix hbonds:

Glycine: the side chain is just a hydrogen and allows water to compete for hbond formation with the polypeptide. The side-chains of all other amino acids sterically block water's access.

Aspartic acid or asparagine: the side-chain oxygen(s) close to the backbone appears from observations to disrupt the hbond on their oxygen and the hbonds on their nitrogen and the cward amino acids's nitrogen. Interestingly glutamic acid or glutamine, identical but with one more carbon in the side-chain, seem not to disrupt.

Histidine: this amino acid appears to disrupt the hbonds on the oxygens of the amino acids 3 and 4 positions nward (towards the N terminus of the polypeptide).

Proline: the side chain loops around and covalently bonds its backbone nitrogen and so prevents any hbonds on that nitrogen. It also forces a kink in the helix.

Cystine, serine or threonine: if the next amino-acid nward is not aspartic acid and the next amino-acid cward is not methionine or histidine, the hbonds on its oxygen and the hbonds on its nitrogen and the nitrogen of the next cward amino acid are disrupted. Serine and less so threonine can sometimes form side-chain hbonds in the middle of a folding event effectively freezing the rotations.

Lysine: its own back-bone nitrogen hbond appears to be disrupted though I cannot see why.

Arginine: though it appears to not disrupt hbonds, it may be able to prevent aspartic acid four positions away from doing so by double-hbonding its side-chain with its own side-chain. It appears this may also occur in other positions in the middle of a folding event effectively freezing the rotations.

No doubt there are other interactions and combination actions to be discovered and these observations may be simplistic or even wrong. Nevertheless applying just these rules, I have a Jmol script that can make the principal folds in the ferritin polypeptide.

The folding script allows rotation on the phi and psi bonds when four hbonds in a row are disrupted as the polypeptide emerges from the ribosome. The script mostly rotates the freed amino acid's psi bond from a dihedral angle of -26 to about +120 as the helix relaxes and unwinds allowing water access to the backbone. The phi bond is mostly constrained by steric affects and only rotates negatively slightly as the amino acid moves from the alpha helix position in its Ramachandran plot to the beta sheet region.