The Poly-Proline Helix Design Series

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Deleted user

Hi all, neilpg628 here to tell you about a new puzzle series we have planned to introduce a secondary structure to Foldit for the first time!

The poly-proline helix

All of the proteins that we have passed to you before have been composed mainly of α-helices and β-sheets. We want to introduce you to the poly-proline helix, which is much tighter than an α-helix, but is less stable because there is no internal hydrogen bonding between residues.


α-helices and β-sheets have hydrogen bonds which keep the structure together. The poly-proline helix has no such bonds

While these helices are typically made almost-entirely out of proline, they can be made out of other amino acids, as long as the bond geometry is roughly the same as that of a regular poly-proline helix. They are found in many proteins, and we want to incorporate them into Foldit to make your contributions relevant to a wider range of proteins!

Unsatisfied polar atoms

Unlike α-helices, poly-proline helices have polar oxygens pointing out from the protein backbone (see above figure). It will be important to satisfy these polar oxygens with hydrogen bonds, to ensure that any protein incorporating a poly-proline helix stays folded! 

These special helices have not been used much in the field of protein design, but they are found throughout nature! Collagen is a protein composed of 3 poly-proline helices, bundled together so that the backbone oxygens can make hydrogen bonds. Collagen has exceptional tensile strength, and is responsible for the toughness of animal connective tissue. 


Collagen’s hydrogen bond network makes it extremely stable even though it is composed of these unstable poly-proline helices

New design puzzles with the poly-proline helix

In our first poly-proline helix puzzle, we’ll provide a small 38 residue protein with a frozen poly-proline helix and designable residues on either side. We want you to redesign the starting structure into a compact protein that can support the poly-proline helix. We're starting with a small protein, but we plan to introduce poly-proline helices attached to larger proteins in the future, to see if you can design more complex poly-proline helix proteins!

Promising designs will be tested in the lab for stable folding! This work could open up new opportunities to apply poly-proline helices in environments where they would not normally fold. Check out Puzzle 1763: Poly-Proline Helix Design: Round 1 now!

Happy designing!

jeff101 Lv 1 

In the poly-proline helix and collagen trimer shown above, 
are there any glycines? Are all the residues shown prolines?
Are the sequences all series of pro-pro-gly triplets? Do all 
of the hydrogen bonds go from one backbone C=O group to another? 
Do any hydrogen bonds go to backbone N-H groups? Do any hydrogen 
bonds go to the nitrogens that are part of the proline rings?

In the image of collagen above, it looks like all 3 strands go 
in the same direction. You can tell because all the proline ring 
nitrogens are located on the right-hand side of the proline rings 
above. Is this correct?

Do all the residues (even glycines) in the poly-proline helix
and collagen shown above lie in the same position on a Rama Map?
Is there one Rama Map position for the prolines and another for 
the glycines?

Thanks!

Deleted user

You are right! This protein consists of repeating Pro-Pro-Gly units.
All hydrogen bonds go from the C=O of a proline to the N-H of a nearby glycine.
The three strands are going in the same direction.
All residues are in the blue region of the rama map.

jeff101 Lv 1

If all the hydrogen bonds go from a proline C=O to a glycine N-H,
does this mean that 2 proline C=O's hydrogen bond to each glycine N-H?
Does this instead mean that half of the proline C=O's don't hydrogen
bond to a glycine N-H? Do any proline C=O's hydrogen bond to the N
of a nearby proline?

bkoep Staff Lv 1

Many of the C=O in collagen make H-bonds with the surrounding water; only some of them bond to the glycine N-H on a neighboring chain.

In a protein chain, the proline N has no hydrogens, so it cannot be a H-bond donor. Technically, the proline N can behave as an H-bond acceptor, but this is very rare (see this reference), and Foldit will not recognize this kind of H-bond.

jeff101 Lv 1 

On Puzzle 1781: Poly-Proline Helix Design: Round 6 
(https://fold.it/portal/node/2008488), the starting 
structure gave the score -221.177 +100 and its residues 
2-34 and 47-79 (all alanines) all gave the same point 
on the Rama Map. Meanwhile, residues 35-46 (a mix of 
alanines and prolines) gave several scattered clumps 
on the Rama Map: one for ala35 ala38 pro41 ala44 ala46, 
one for ala36 ala45, one for ala37 pro43, and one for 
pro39 pro40 pro42. 

Why didn't alanines 35-38 and 44-46 give the same spot 
on the Rama Map as alanines 2-34 and 47-79? Why didn't 
prolines 39-43 all give the same spot as each other on 
the Rama Map? Why were prolines 39-43 scattered into 
3 different clumps on the Rama Map? 

Did the Rama Map positions for residues 35-46 really 
come from the sequence AAAAPPPPPAAA? If not, what was 
the actual sequence that gave these Rama Map positions? 
If the actual sequence was made from PPG repeats, what 
were the residue numbers for the glycines, which Rama 
Map clumps were for the glycines, and which Rama Map 
clumps were for the 2 different kinds of prolines? 

Thanks!