Sul forum di rosetta, alcuni dei piani futuri del progetto:
One promising avenue for future research is to use this computational technology to design specific inhibitors of proteins that are important regulators of cellular activity but where experimental research has been stymied by the lack of specific, non-toxic effectors. Let's take a few steps back and try to see the broader picture. Our understanding of molecular biology progresses through the identification of key players and systems in the cell and then by modulating these effectors and observing the results on cell viability and function. This process parallels the concept of reverse engineering of mechanical and electronic systems.
A major tool in this process involves the use of genetic knockouts. These are mutations to genes that disable a protein's function. Using this technique myriad gene functions have been described, including genes that are important tumor-suppressors or promoters, metabolite importers and regulators of cell size, form, and fate. But, gene knockouts are not very subtle tools and they often have far-reaching consequences on cell viability, making it difficult to interpret the results of the knockout experiment. For a beautiful and accessible description of the parallels between reverse engineering and molecular biology and where the difficulties lie, see "Can a Biologist Fix a Radio?" (Biochemistry (Moscow), Vol. 69, No. 12, 2004, pp. 1403-1406; protein.bio.msu.su/biokhimiya/contents/v69/pdf/bcm_1403.pdf).
One way to deal with these difficulties is by using specific inhibitors that are invoked at specific times to block a certain protein function rather than pulling the brakes on a protein from the cell's inception. The ideal inhibitor would selectively modulate one interaction without affecting other interactions, thus allowing a subtle study of the significance of interactions in the cell. Thus specific inhibitors, where they have been discovered and deployed, have yielded very important lessons on the function of proteins that are crucial in many cellular signaling pathways, to give but one example. But, these inhibitors are rare and very difficult to identify. We think that similar to the influenza binder, we should be able to use computational protein design to generate novel and highly specific protein inhibitors of important cellular players and help in elucidating their functions.
Over the next few weeks we will launch new jobs on Rosetta @ Home that target proteins where an inhibitor could help make progress in our understanding of cell biology. As we prepare each of these targets for Rosetta @ Home we will describe the rationale for pursuing them in this thread.
One of these targets is RhoA. This protein belongs to the family of oncogenic Ras proteins which are involved in cell division and regulation. RhoA is known to be a major player in cancer. As mentioned above, knocking out RhoA causes many different problems for cell viability. It is easy to understand why if you merely look at the number and variety of its interaction partners (see, en.wikipedia.org/wiki/RHOA)! By generating a specific inhibitor of RhoA we hope to enable probing the effects of its modulation at specific points in the living cycle of the cell and under different conditions -- studies that are nearly impossible to perform today.
Finally, I'd like to thank all of the participants in Rosetta @ Home for the immense boost in computational throughput over the past few weeks! Without the 40% increase in computational power it would have been impossible for us to work on these targets in parallel to the needs of the group who are working on CASP! Please keep these contribution levels!
Alcune cose tecniche, ovviamente, mi sfuggono, ma il tono generale sembra quello di eccitazione generale, soprattutto per il boost prestazionale (dovuto al Penthatlon) che sperano duri a lungo...