Posts by gregorio

1) Message boards : Rosetta@home Science : Q about the native shape (Message 75810) Posted 26 Jun 2013 by gregorio Post: Armando, those are both excellent questions. I'll answer the first one here. It turns out that many natural proteins move as part of their natural function -- here the most obvious example would be muscle proteins, like myosin, that change shape in order to exert a pulling force and result in muscle contraction. Therefore any of these proteins have multiple shapes that they can adopt with the same sequence. Usually the change in shape is triggered by a small chemical change, like adding a phosphate group (a phosphorous atom surrounded by negatively charge oxygen atoms) to one of the amino acids in the protein. Some good examples of proteins that change shape would be DNA polymerases (enzymes that copy DNA), motor proteins (myosin, kinesin), and pumps, like the F1F0-ATPase. Here's a review on the topic of protein structural changes: http://www.sciencedirect.com/science/article/pii/S1367593103001753 Here's a more general article on proteins that have very similar sequences but different shapes: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2673347/ However, given these examples of proteins that change shape, or similar-sequence proteins that have different shapes, it is still safe to say that most proteins have one most stable shape that they tend to adopt. This is the "lowest energy" state, and for almost all cases for which we use rosetta-at-home we know that the protein in question does actually fold in to one unique shape.
2) Message boards : Rosetta@home Science : Quantum computing and Rosetta (Message 75809) Posted 26 Jun 2013 by gregorio Post: boboviz to answer your question: GPU code for Rosetta is not being actively pursued in our lab. Will posted lots of stuff about his work for GPUs a few days ago, but as he says what he did ends up being very specialized and is not of general use. We are pursuing lots of other algorithm improvements, including Will's work, that use standard CPUs and we think that in many cases we are more limited by our ability to come up with correct and fast algorithms than we are by anything that could be solved with a GPU. That being said, rosettaathome is an incredibly powerful tool for us to develop new algorithms with, and many of us are working on new algorithm development.
3) Message boards : Rosetta@home Science : Q about the native shape (Message 75755) Posted 12 Jun 2013 by gregorio Post: This is Lucas from the Baker lab, wanted to give a more detailed answer on this. We are primarily engaged in a few tasks here, all of which we use boinc for: 1) Making better algorithms to predict structures. Mod.Sense pointed this out. Much of the use of boinc is to test out variants of algorithms, totally new ideas, etc. 2) Improving the scoring functions in those algorithms. This gets pretty technical, but you can think of Rosetta software as a search algorithm -- it needs to look around (sampling) and it needs to evaluate what it finds (scoring). Boinc is used to test new methods of scoring, aka new ways to evaluate structures. These methods help structure prediction (1, above) and sequence design (3) below. 3) Design of new proteins for new tasks. This is the inverse of problem (1) where we know the sequence and are predicting the structure. Here we have a structure, or multiple structure ideas, in mind and we want to design a protein that takes on that structure. The structure could be an influenza binder, or a new enzyme to treat a disease. We run Rosetta algorithms to design new sequences for a given structure, and often run that on boinc. 4) When we make a new design, how do we know that it will look the way we want it too? Well, we put it back in to step (1) on boinc, to test if it is at least self-consistent. If boinc doesn't give us back the structure we are trying to make, we might be in trouble. The majority of folks here in the lab are working on (3) and some are doing (4), and many of us use boinc as a vital tool to make design and design evaluation possible.
4) Message boards : Rosetta@home Science : Quantum computing and Rosetta (Message 75653) Posted 22 May 2013 by gregorio Post: Hello, this is Lucas from the Baker lab. Interesting thread, unfortunately quantum computing is not currently on our radar, but the work from Aspuru-Guzik's group certainly points to interesting possibilities. Two issues here: 1) GPU computing is much closer to reality for Rosetta, as it is completely routine for many other compute tasks. There is actually some preliminary work on this for Rosetta from a couple of developers as many tasks are amenable to GPU algorithms. It is just preliminary, proof-of-concept, and the fact is that as an academic group there is not a ton of man-power around to devote to the coding task of fully implementing this work. Could happen soon though. 2) The Aspuru-Guzik work focuses on a simplified model of protein folding that was popular in the 1990s, lattice proteins. These are a theoretical construct designed to study the process of protein folding, not for structure prediction or design. The big names here are Ken Dill, Jose Onuchic, Peter Wolynes, Eugene Shakhnovich -- lots of interesting work about the theoretical properties of proteins and their folding pathways. It is very beautiful work that related very closely to experimental findings in the 1990s from Alan Fersht's research group, so-called "phi-values" and protein folding transition states. But I digress... Currently in the Baker lab we are not focusing on the folding problem so much as the structure prediction and design problems. Here lattice models are not useful, but instead we do (drumroll) off-lattice, rotamer-based models. The types of tools Aspuru-Guzik and co-workers developed for quantum computing could be adapted to off-lattice, so thank you for pointing that out. This will be on the radar eventually, but is currently we have a ton of algorithm work to figure out before we start on the quantum computing.
5) Message boards : Rosetta@home Science : DISCUSSION of Rosetta Insight (Message 75642) Posted 20 May 2013 by gregorio Post: Hello, this is Lucas, I'm a postdoc in the Baker lab and a new scientific user of Boinc for design of novel proteins. We are pushing for more communication on our end and part of that is more updates here on these boards, but also reviving our twitter feed @rosettaathome. That will include updates on papers published using boinc, and more small updates of progress, interesting results from a few days' worth of boinc results, etc.
6) Message boards : Rosetta@home Science : Design of new fluorescent proteins (Message 75641) Posted 20 May 2013 by gregorio Post: Hi, this is Lucas, I'm a postdoc in the Baker Lab working on enzyme design, design of ligand binders, and some design algorithms, especially applying very simple learning approaches to protein design. For the last few months I have been working with Yakov Kipnis in the Baker lab on the design of completely de novo fluorescent proteins. If you are familiar with Green Fluorescent Protein and its relatives (Yellow, red, etc.) you know that these proteins are workhorses of modern biology. They make very small sub-microscopic things visible inside a cell or tissue, and work on these was awarded a Nobel prize a couple of years ago to Roger Tsien and co-workers. Now with the power of recent advances in Rosetta in the design of de novo proteins we are trying to create entirely new, and better, fluorescent proteins. These will be brighter and last longer. They will be more controllable by the researcher, for example having the ability to turn "on" upon command, something that would make lots of biologists happy. If we are successful, we hope that these will be useful for lots of cell biologists and biotechnologists. We envision their use for very sensitive medical testing and diagnostics, both ex vivo (for example blood tests) or in vivo. We are especially excited about those medical applications -- our proteins could make a tumor glow under UV illumination, so a surgeon can carefully remove it without damaging nearby tissue, but also without leaving any tumor behind. And we hope that once these proteins become available, lots of other medical applications -- that are currently imposible with existing fluorescent proteins -- will become feasible. We also think it would be incredibly beautiful and powerful to create a new class of glowing proteins.
7) Message boards : Rosetta@home Science : Twitter feed @rosettaathome (Message 75640) Posted 20 May 2013 by gregorio Post: In an effort to adopt the technology of the early-twenty-teens, and to help facilitate communication, we're going to be sending more short updates about Rosetta at home science on our twitter feed @rosettaathome. Many of you are already likely subscribed, but if you are interested please follow us on twitter. We'll of course continue to post longer-form updates here, but we're hoping to increase our frequency of updates to the user community through twitter.