Posts by Vanita
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1)
Message boards :
Rosetta@home Science :
FAQ on diseases being explored by RAH is out of date
(Message 43780)
Posted 16 Jul 2007 by Vanita Post: Aah, I see the point you are making. I'll leave it to the people who are maintaining this site to update teh FAQs etc, but what I can tell you myself is that the Disease related research page, at least as it pertains to work being done within the lab, is not out of date; ie we are still working on cancer related projects, as described. The FAQ was put together by a user who was quoting the disease related research page, and he chose not to quote the whole page. Not all the projects listed on the disease related research project are actively using RaH resources at any given time. For example, I am working on the Prostate Cancer project at the moment, and I'm happy to report I'm not using any computational resources at all as I have now progressed to the experimental part of this project. I know this doesn't address your concern about wanting to know how each work unit relates to disease, but I hope at least it helps temporarily. Cheers, V. |
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2)
Message boards :
Rosetta@home Science :
joining 2 portions of proteins using phi and psi angles
(Message 43574)
Posted 12 Jul 2007 by Vanita Post: Kamal, if you want to build some missing density between two portions of a protein using phi/psi angles, the second half will generall move relative to the first half, unless you idealize all the backbone torsions firts. Hope that helps. |
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3)
Message boards :
Rosetta@home Science :
FAQ on diseases being explored by RAH is out of date
(Message 43573)
Posted 12 Jul 2007 by Vanita Post: Hi Greg, Can you point out the contradiction to me? |
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Message boards :
Rosetta@home Science :
Top 7
(Message 37604)
Posted 8 Mar 2007 by Vanita Post: you got it right ;-) And it was a really insightful question to begin with. I'm always impressed at how all of you guys are really looking at the details. V. I'm sure that they have would have access to the genetic code and therefore the protein sequences, too :) |
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Message boards :
Rosetta@home Science :
Top 7
(Message 37552)
Posted 6 Mar 2007 by Vanita Post: Hi Hugo, Xray crystallography relies on the fact that each asymmetric unit in a protein crystal is identical to the next. In reality, there are often some atoms within the protein that are disordered and are in different conformations in each assymetric unit. These atoms cannot be resolved within the electron density, and are therefore not included in the final model. It is better to truncate amino acids to the part that can be modeled with certainty than to include atoms that are unresolved in the density and give the impression that they are well ordered when they are not. All amino acids (except Gly) are identical up to the C-beta (CB) atom. The differences become apparent in the atoms that are further from the backbone. Cheers, V. |
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6)
Message boards :
Rosetta@home Science :
Scientists Unveil Piece of HIV Protein that May Be Key to AIDS Vaccine Development
(Message 36962)
Posted 19 Feb 2007 by Vanita Post: Hi, We are using this structure as well as others as starting points for vaccine design. It's pretty exciting stuff, and I'm happy to say I've now officially joined the efforts on this project. Specifically, I'm using a similar crystal structure (solved by the same NIH group, our collaborators) in which a human immune-cell protein (CD4) interacts with parts of GP120 in a similar fashion to B12. Designing vaccines using this structure is analogous to (and being done in parallel with) using the B12 structure, and is a an extra chance at hitting the jackpot, ie designing an effective vaccine to elicit neutralizing antibodies. Cheers, V. |
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7)
Message boards :
Rosetta@home Science :
Does the N-terminus fold first?
(Message 35570)
Posted 26 Jan 2007 by Vanita Post: Thanks for the info, particularly that on chaperones. Maybe there should be something in the FAQ about them? Hmmm, I admit it, I am guilty of oversimplification. You are right, this is idea is testable, and has been tested, at least after a fashion, and the conclusion is a little more broad than you might expect. It turns out that when you separate proteins by whether they have more long-range contacts or more short-range contacts (a quality we call contact order), the ones with lower contact order (more short-range contacts) fold faster. This applies not only to short-range contacts within the N-terminus, but throughout the length of the protein. Here's the trick: while some proteins may use low contact order as a way of facilitating their folding to the native state, there clearly are proteins extant that have all sorts of contact orders, including high contact orders (where, for example, the N- and C-termini might interact) and they all fold to their native states. So while contact order can be a useful predictor of topology for some proteins, it is important to balance the weight placed on contact order with other physical-chemical qualities that will apply to all proteins regardless of topology. I do believe contact order is one of the terms in the ab initio scoring function, so it's not ignored. Hope that helps! V. |
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8)
Message boards :
Rosetta@home Science :
Does the N-terminus fold first?
(Message 34987)
Posted 17 Jan 2007 by Vanita Post: Rosetta does not assume that the N-terminus folds first. Is this a valid assumption? In almost all cases, the answer is, yes, it is a valid assumption. Even though the protein is synthesized from N to C, as nicely described by CJ below, this shouldn't affect the final folded structure for a couple of reasons which I will try to explain. 1) the native structure is at a thermodynamic minimum of the energy landscape. That means that no matter what route the protein takes (ie fold N first, or fold C first, or fold some other part first) given enough time it will find the lowest energy native conformation. 2) It is true that for some proteins, if they fold the "wrong" part of the protein first, they might become kinetically trapped in the incorrect conformation. That is, the amount of time it would take for the protein to unfold the incorrect structure and refold into the correct structure is too long on the time scale of the cell to be reasonable. So the cell has evolved mechanisms to overcome this. The main such mechanism is the "chaperone". The chaperone: a large protein complex whose purpose is to help other proteins fold properly. Some chaperones work by providing a closed environment in which a protein can quickly and safely sample different conformations, until is finds its native conformation and is released by the chaperone to do its job. It allows the protein of interest to escape from kinetic traps and find its thermodynamic minimum. The key thing to remember is that Rosetta basically ignores kinetics and focusses on thermodynamics. V. |
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Message boards :
Rosetta@home Science :
Genetic,Stemcell and Rosetta
(Message 34852)
Posted 15 Jan 2007 by Vanita Post: Hi Ed, Check out our Disease Related Research. Currently, the use of protein structure predction and design for health related applications is a complement to, not a competitor of, the other fields you mentioned. If you have more questions after reading the above page, feel free to post again. Vanita. |
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10)
Message boards :
Rosetta@home Science :
Solid answer needed, for who do we do this?
(Message 25382)
Posted 29 Aug 2006 by Vanita Post: Rosetta at home is freely available (including the source code) to academic users. Companies are required to pay a fee to use it because they will be profiting from it so it is only fair. Besides, most companies probably need to pay a fee so that if they do develop a marketable product using the software, they will not have any problems with their lawyers telling them they should have bought the rights first. The main reason that the source code is not easily available to everyone else is because people on these message boards expressed concerns that there is a small but significant fraction of people who would exploit the source code to increase their BOINC credits or do other mischief. It seems reasonable that the risk of harm to the Rosetta@Home community should be minimized. As far as cures for various diseases goes, any company that licences Rosetta and develops a drug using Rosetta will be free to patent the drug (but will have no rights over Rosetta itself) and make whatever profit it sees fit. As for therapeutics that we in Bakerlab and collaborating labs are working on, nobody here is doing this to get rich. We are doing this because we believe we can make a contribution to the world, and help people who desperately need help. Case in point: AIDS drugs (eg "protease cocktails") that are the current best treatment for HIV/AIDS cost thousands of dollars per month of use, and are out of reach for most third world patients. We are trying to develop a vaccine which would be cheap and effective, and would directly help those who suffer most from the scourge of HIV. I hope that clarifies things a little. |
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11)
Message boards :
Rosetta@home Science :
Questions about protein folding
(Message 21868)
Posted 4 Aug 2006 by Vanita Post: Frank, you've hit on something that is in fact a big bone of contention among CASP participants (so I've heard, at least, I've never participated myself). RMSD is generally agreed to be a suboptimal measure for determining how close to correct a prediction really is. One example where it would fail is the one you gave below, of two domains with a flexible linker between them, and which in solution may adopt different internal orientations. Another example is that RMSD indiscriminately rewards more compact structures. As far as I know, the debate on the "best" measure of correctness occurs at every CASP, and there has been no consensus so far. |
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Message boards :
Rosetta@home Science :
Suggestion: Include diabetes in disease related research.
(Message 21486)
Posted 31 Jul 2006 by Vanita Post: While you're on the topic of cancer, I happened to see this news Friday: Yeah! This is an exciting development! And if I'm not mistaken, much of the work to develop this vaccine was done right here in Seattle! |
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13)
Message boards :
Rosetta@home Science :
Suggestion: Include diabetes in disease related research.
(Message 21175)
Posted 25 Jul 2006 by Vanita Post: Sorry for the delay in replying ... busy here. How different is the androgen receptor protein in the male prostate different than a similiar protein in a female that has an estrogen receptor? I ask this because there are several well known treatments for post-menopausal women to prevent breast cancer (Tamoxifen, Arimidex, Aromasin) however I do not know of any medications treating older males that are at risk for developing prostate cancer? Actually AR and ER proteins are evolutionarily related, and *very* similar in structure and function. As you correctly imply, what works for breast cancer should work for prostate cancer, because the proteins are so similar. Currently, the main treatments of prostate cancer include surgery (to remove the tumour), radiotherapy (to blast the tumour) and hormone therapy (to deprive the tumour of the signals it needs to grow). Hormone therapy in prostate cancer includes a variety of drugs that target different parts of the testosterone pathway, including LHRH antagonists (which are upstream of the testosterone synthesis pathway), steroidal anti-androgen hormone therapy, and non-steroidal anti-androgens. This is similar to anti-estrogen drugs. The problem with hormone therapy is that the tumour often becomes resistant to it. So it is usually very successful as a first line of treatment, but if/when the cancer recurs, the tumour is unresponsive to a second treatment of hormone therapy. Also, because of the side effects of hormone therapy, it is only used as a treatment for prostate cancer after diagnosis, never as a preventative for someone who isn't already sick. The tie-in to diabetes (since this is the diabetes thread), is that type II diabetes involved PPAR-gamma, another close relative of ER and AR, and similar anti-PPARgamma therapies may be possible for this disease, analogous to anti-androgen and anti-estrogen therapies for cancer. I hope that answers your question, if not feel free to ask again. Cheers, V. |
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14)
Message boards :
Rosetta@home Science :
Suggestion: Include diabetes in disease related research.
(Message 20011)
Posted 10 Jul 2006 by Vanita Post: Haven't been on the msg boards much lately, but saw your question today. Will answer properly when I have time this week. Cheers, V. Vanita, |
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15)
Message boards :
Rosetta@home Science :
What is a flexible backbone protein?
(Message 19815)
Posted 6 Jul 2006 by Vanita Post: Bonjour Olivier, Merci pour tes questions et pour traduire notre site en francais! Je pense que tu comprend le biochimie bein mieux que je comprend francais (excuse ma mauvaise grammaire et ortho, svp), mais quand meme j'aimerais bien lire ton site de web en francais, quand tu a fini faire la traduction. Thanks Christoph for taking time and effort to explain things so well! I'm well behind, and there's not much left to explain, nonetheless, I thought I'd chime in to add a little more detail to the discussion of amino acids, residues, sequence and structure. OK, I have a few more questions... Christoph's diagram explains the difference between the main chain (the backbone) and the side chains (the "R" moieties). A further explanation that may help is that protein structure can be described at 4 different levels. The PRIMARY STRUCTURE is given by the sequence of amino acids (the order of different R groups). It consists of the chemical structure of the protein and the only thing you need to add to the diagram below would be to replace the R symbols with the actual atoms that they represent. So for example a simple 3 residue peptide represented in text like this: Alanine-Serine-Cysteine, would have a primary chemical structure comprised of 3 of the monomer units in the diagram below, where the first R would be replaced by a methyl group (a carbon and 3 hydrogens), the 2nd R would be replaced by a carbon and an alcohol group, and the 3rd would be replaced by a carbon and a sulfur. The SECONDARY STRUCTURE describes the local conformations of the primary structure: the helices mentioned below are an example of secondary structure. You need more than just the chemical formula to visualize the secondary structure, you need to see interactions between residues. The TERTIARY STRUCTURE describes interactions between residues that are far from each other in sequence. In the linear chain below tertiary contacts can occur between residues that are separated in chain by 5 peptides bonds, or more (up to hundreds). Together, the primary, secondary, and tertiary structures, if known, define and describe the 3D structure of a protein. The QUARTENARY STRUCTURE is the final, highest order description of structure, and this describes the interactions between protein molecules - eg two proteins that are not linked to each other by bonds like the ones described by lines in the figure below, but which nonetheless come together to form a "dimer". The quartenary structure is often important in biology, as little "molecular machines" are built from complexes of proteins. There is a mode of Rosetta which examines quartenary structure, and tries to predict which proteins will interact and how they interact. If it’s not too much bother for you, could you give a simple example of the flexible backbone protein design process? Je pense que Christoph a donner un tres bon example du FlexBB design. Moi je essaie de developer les methodes de faire le FlexBB design, et c'est tres difficile! Il y a plusieres methodes qu'on essaie, mais le methode qui a eu le plus de succes est celle qui est decrit par Christoph. Si tu te sent un peu brave, tu peu aussi lire le papier du Brian Kuhlman sur le design d'un proteine completement nouvelle, qui a jamais etre vue en nature, et qui a ete cree par le FlexBB design. Le pdf du papier se trouve sure le site de web du Baker lab. Le papier a ete publis en 2003: Kuhlman, B., Dantas, G., Ireton, G. C., Varani, G., Stoddard, B. L., Baker, D. (2003). Design of a novel globular protein fold with atomic-level accuracy Science 302, 1364-8. What are the residues of the sequences of a protein then? Are there really side chains, or are all chains equally important for the structure? Yes the side chains are important for all aspects of protein structure. The chemical nature (sequence) of sidechains is the full description of the primary structure. The size of the side chains restrict which secondary structures are allowed. The non-covalent chemical interactions between side chains specifies the tertiary structure. Also, you may look at a previous post, as well as the science FAQ. Mais je pense que les explications donner par Christoph sont bein meilleure que les miens ;-) |
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Message boards :
Rosetta@home Science :
Rationale behind protein shape prediction projects
(Message 10800)
Posted 16 Feb 2006 by Vanita Post: Once all proteins' shape has been solved experimentally, then there will be no need for projects like HPF, right now using Rosetta sw to determine shape mathematically. True, if all proteins of interest are solved experimentally, Rosetta will become redundant. But on the other hand, if Rosetta accurately solves all the remaining protein structures, then experimental techniques will become redundant ;-) Actually, it probably makes more sense to fill in the blanks in the PDB computationally, rather than experimentally, because computational structure prediction takes far less time, money and effort than experimental structure determination. Protein design is of course an ongoing effort in Bakerlab and other labs; as you point out, even when the structure of all natural proteins is known, there will still be a use for Rosetta in designing novel proteins with specific functions. Not sure how long it would take to "finish" the PDB experimentally; as mentioned below, it's not clear that all proteins can even be solved experimentally. Hope that helps! |
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Message boards :
Rosetta@home Science :
DNA
(Message 10600)
Posted 9 Feb 2006 by Vanita Post: Ok. I hope that in the future there will be, because cancer and getting older depending in the biggest on DNA mutations. Is it true? There almost certainly will be DNA jobs on boinc in the future. As for aging and cancer, well, as usual there is no one simple answer. But the "short" answer is that cancer indeed is the result of mutations at the DNA level, often multiple mutations (what's known as the "2-hit hypothesis"). However, in order for these mutations to actually cause cancer, they must activate a gene expression program that depends on the action of several proteins. Therefore, targeting the DNA for repair (gene therapy) is one approach for cancer treatment, but another approach (and perhaps more feasible in the short term) is to target the proteins involved in uncontrolled cell growth. As for aging, an accumulation of mutations may contribute, but currently the main hypotheses are 1) The inactivation of telomerase, a protein-RNA complex that maintains the ends of our chromosomes, causes cells to senesce (stop growing and renewing). 2) Certain genes exist which limit growth and renewal, leading to aging. This is not a bad thing, as aging is a natural process, and if the genes involved in stopping cell renewal were to be inactivated, it almost surely would increase the incidence of cancer. Cancer is a form of immortality; cells have escaped the control of telomerase and other "aging" controls and so grow out of control. Random trivia: one of the most common cell types used in human tissue culture experiments is the "HeLa" cell line. This cell line came from a woman, Helen Labelle, who died of cervical cancer in the 1960's. So cancer cells can (apparently) be immortal. But aging is a natural proceess and most biomedical research is aimed at eradicating the diseases of again (Alzheimers, cancer, etc) not at "curing" aging itself (though of course that is also being looked at). |
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18)
Message boards :
Rosetta@home Science :
Suggestion: Include diabetes in disease related research.
(Message 10529)
Posted 7 Feb 2006 by Vanita Post: One of the things I ran into over at FaD was that FaD has a collection of diabetes related structures that need to be tested out and seen if they're useable for diabetics. do you have a link for this? thanks to everyone's posts here, I am becoming more and more interested in learning about diabetes ... |
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19)
Message boards :
Rosetta@home Science :
Rationale behind protein shape prediction projects
(Message 10490)
Posted 5 Feb 2006 by Vanita Post: Wow, this post brings us a number of excellent and insightful questions. I can't do justice to all of the points raised in full, but will try to address some here. Just wondering. There is a PDB database out there. It contains information about 3D structures of different proteins. So far it accumulated info about >30 000 proteins. In human DNA it is believed to be around 30 000 - 40 000 genes, so it is 30 000 - 40 000 structures we need to know. ... most important ones must be already in there. Many of the structures in the PDB are "repeats" - ie multiple structures of the same protein, with variations on origin (which species it comes from), or point mutations (single amino acid changes which do not alter the 3D structure). So we have very good coverage of a subset of human proteins, but large sets of proteins are still missing from the PDB. These under-represented proteins are slowly being filled in by x-ray crystallographers, but they are difficult to study experimentally, and some may never be crystallized or may always be too big to study using NMR. Also, minor point, but although the number of human genes is approx 30 000, the actual number of proteins (the human "proteome") is larger (due to processes such as alternative splicing). And those data way more accurate than results of this project. Currently experimental structure determination is more accurate than Rosetta, but Rosetta is getting closer. See recent paper by Bradley et al on progress in high resolution modelling. Bradley, P., Misura, K. M., Baker, D. (2005). Toward high-resolution de novo structure prediction for small proteins Science 309, 1868-1871. [Full Text PDF] The level of accuracy obtained for some of the proteins is as accurate as experimental techniques. Furthermore, if someone would need structure that not in PDB, he most likely will use newer version of Rosetta. Which should produce more accurate results - Rosetta is under development and quality of predictions grows ... So one way or another results of this project would be obsolete and outdated in 2-4 year time. What the point of project? That is the point of the project - to improve Rosetta and increase the quality of structure prediction to the level obtained for some proteins in teh Bradley paper, and the level of experimental structure determination. But Rosetta needs to be improved in order to accomplish this goal for all proteins. Again untrue, because of two things: Again, I am impressed by your insight! However, although it is technically true that crystal artifacts can occur, in practice the crystal structure is almost always a biologically relevant structure, and identical (within experimental error) to the structure determined by solution phase techniques such as NMR. As far as I understand how Rosetta works, it uses known kinetic and energetic models ... Actually, Rosetta looks only at the energy of the final folded state, and not the kinetics of folding. Although there is a correlation between some aspects of structure and folding kinetics (and you can find papers on that on the bakerlab home page) the actual kinetics of folding are not taken into account during structure prediction by Rosetta. |
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20)
Message boards :
Rosetta@home Science :
Suggestion: Include diabetes in disease related research.
(Message 10486)
Posted 5 Feb 2006 by Vanita Post: Hi folks, Please continue to post here questions and suggestions on diabetes research and how Rosetta may (in future) help with the battle against this disease. I've moved the more philosophical discussion to this thread in the Cafe Rosetta message board. Thanks, V. |
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