Osteogenesis Imperfecta, collagen, and molecular pucker

[Jesse_V]

Hi there, I'm kind of confused, and I'm hoping someone can help me out here. I'm trying to understand F@h's work on Osteogenesis Imperfecta and the molecular processes involved there. It appears that mutations in collagen are the key here. From the Diseases Studied FAQ, it appears that there were two papers that were accepted for publication, but only one actually came out. A search for "collagen" on the Results (Papers) page turned up only one paper, namely this one. While I understand that F@h's pursuits into OI are a pilot project compared to research into Alzheimer's and Huntington's, I'd still like to understand the significance of their simulations and their impacts into disease research. So I pulled up the paper and tried to figure things out. But even the Abstract, Introduction, and Conclusions proved way too complex for my comprehension. If someone can explain to me the medical implications of this paper and what it was studying. My main problem here is that I have a very limited biochemical vocabulary. I'm running into things like this:

Abstract: Recently, the importance of proline ring pucker conformations in collagen has been suggested in the context of hydroxylation of prolines. The previous molecular mechanics parameters for hydroxyproline, however, do not reproduce the correct pucker preference. We have developed a new set of parameters that reproduces the correct pucker preference. Our molecular dynamics simulations of proline and hydroxyproline monomers as well as collagen-like peptides, using the new parameters, support the theory that the role of hydroxylation in collagen is to stabilize the triple helix by adjusting to the right pucker conformation (and thus the right angle) in the Y position.

and

Concluding remarks: We have developed a new set of molecular mechanics parameters for hydroxyproline that reproduces the correct pucker preference. Our MD simulations of collagen-like peptides using the new parameters support the importance of pucker conformations in the stability of the collagen triple helix. We believe the new parameters will be useful for computational studies of collagen.

What is "proline ring pucker" and what is "hydroxyproline" and why is it important? I did however run into Project 1001's description: http://fah-web.stanford.edu/cgi-bin/fah ... ned?p=1001 which was very helpful in explaining collagen and a tiny bit of info about its role in diseases. My main science question is the significance of the paper, what scientific problems it is addressing, and what these words mean. I found this on the Results page: "SUMMARY: Simulation of the collagen triple helix has been given less attention than more common protein 'folds.' Here we present newly derived parameters for such simulations to gain better agreement with experimental data, and thereby offering insight into the stability of the triple helix structure." But I'm still confused. Can someone please explain? Biochemists, I welcome your company. Thanks.

[Jesse_V]

I understand that this is pretty technical, it's around Christmas Break, and that we're all volunteers here. I'm hoping that there is some biochem majors here that might be able to give some helpful insights to this paper. I'm looking forward to figuring this out, it looks really impressive!

[selkieupsilon]

Hello! Sorry for posting on a super-old thread, but I can answer some of these questions (if you are still interested and haven't already figured it out). Also thought might be useful if someone ends up here by searching...

Trying to answer the above:

Collagen is the major structural protein in the human body. Like all proteins, it is made out of amino acid building blocks. Specifically, the amino acid composition of collagen contains a high proportion of glycine, proline, and hydroxyproline. Hydroxyproline is similar in chemical structure of proline, but has an extra hydroxyl (-OH) group attached to a particular carbon on proline. While this might seem like a fairly small change, attempts to make collagen that doesn't contain hydroxyproline is found to be weaker than normal collagen. So hydroxyproline is important for collagen to carry out its structural role. The problem was that it was unclear how it "worked".

One of the ways of understanding how proteins work is to carry out computer simulations of proteins, like what is done in F@H. However, the computer needs to be given rules and parameters about how bits of the protein (i.e. the amino acid building blocks) behave before it can carry out the number-crunching. The special thing about proline (and hydroxyproline) is that there is a 5-membered ring (4 carbons, 1 nitrogen) in this amino acid. Moreover, this ring forms part of the protein backbone. Usually a protein might be thought of as a long, floppy chain before it folds into the correct structure, but this is not true at places where you have proline/hydroxyproline as the building block, because the ring restricts how much that bit of the backbone can move. Since it is a 5-membered ring, the rules of chemical bonding indicates that this ring will not be flat, instead it will have a "bend", which is what is known as the pucker. Because the proline ring is not symmetrical, puckering one way or the opposite way gives different allowed ranges of movement to the protein backbone (this bit is a little inexact). It was known that one of the key differences between proline and hydroxyproline is the way they prefer to pucker, which means that having proline and hydroxyproline has different restrictive effects on the collagen protein backbone, and likely play different roles in collagen stability.

Previous attempts to include hydroxyproline in calculations have not given the correct pucker as is known from experimental studies. Therefore, this paper presents a new sets of parameters which is shown to give the correct pucker, and therefore is particularly suitable for calculations that involve collagen proteins.

I hope this helps!