Loops to tie a knot in proteins?

By Grant Jacobs 30/07/2010

Most proteins fold onto themselves without forming knots. A minority form a ’topologically entangled conformation’, a knot.

Proteins are strings of amino acids, chained together one after the other.

(Source: WIkimedia Commons.)
(Source: WIkimedia Commons.)

The properties of proteins depends on their specific three-dimensional fold, how the chain of amino acids are arranged in space.

When proteins are first made by reading the RNA copy of a gene, the order of the adjacent triplets of RNA bases (letters of the RNA code) specify a specific order of amino acids, one amino for each particular triplet of bases.

This initial chain of amino acids is just that, a linear chain.

Proteins fold through the physical properties of the particular sequence of amino acids making up the protein inducing a particular collapsing of the protein on itself in water.

For the vast majority of proteins this collapsing on itself does not involves a portion of the chain threading itself through another portion of the chain to form a knot.

Intuitively this makes sense; self-knotting of a protein chain would be more finicky that simply placing portions of chain adjacent to other portions of the chain.

A few proteins, however, manage to pull off this self-knotting feat.

Being able to accurately predict the folding of a protein from it’s amino acid sequence, to solve the ’protein folding problem’ would open door to designer enzymes and vastly increase our understanding of life through having available the detailed chemical arrangement of proteins in 3-D.

In this cartoon of a protein, the grey tubes represent loops connecting the more compact helical and ribbon (red arrow) regions of this small portion of a protein (Source: Wikimedia Commons.)
In this cartoon of a protein, the grey tubes represent loops connecting the more compact helical and ribbon (red arrow) regions of this small portion of a protein (Source: Wikimedia Commons.)

Examining knotted proteins, with their potentially more finicky folding requirements, might be another way to explore the detailed basis protein folding.

What features might guide self-knotting in proteins and can they teach us something about how proteins fold?

European computational biologists compared proteins that form knots and those that do not, looking for features that might be associated with knot formation.

For the most part the amino acid sequence of the proteins did not distinguish knotted proteins from those without knots.

Comparing the 3-D structures of proteins, in particular those with similar overall folds but with one case being knotted and the other not, their work suggested particular loops on the surface of some the proteins examined are a feature common to knotted proteins not found in unknotted proteins.

These might be, in their words, ’knot-promoting’ loops, in some way these loops may be aiding the chain in threading through itself.

(Source, Fig 1 of Reference.)
(Source, Fig 1 of Potestio et al, see References.)

I’ve no doubt that researchers will now look very closely at these particular protein loops and see if they do in fact promote the formation of a protein knot.


Potestio, R., Micheletti, C., & Orland, H. (2010). Knotted vs. Unknotted Proteins: Evidence of Knot-Promoting Loops PLoS Computational Biology, 6 (7) DOI: 10.1371/journal.pcbi.1000864

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