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posted 01. February 2003 22:21
The Scientist Volume 17 Issue 2
http://www.the-scientist.com/yr2003/jan/lcprofile1_030127.html
Unraveling Protein-Protein Interactions
New genome-scale approaches expose the wiring of multiprotein complexes on a cellular scale
By Leslie Pray
[1st two paragraphs]
Using a computer instead of a pipette, Jeffrey Skolnick contemplates the subtle forces that bring proteins together. His first computational forays helped decipher the quaternary structure of proteins--the interactions between subunits in molecules such as tropomyosin. Now Skolnick, executive director of the Buffalo Center of Excellence in Bioinformatics, Buffalo, NY, works on a far bigger problem: understanding, modeling, and predicting the currently unfathomable rules of etiquette that govern protein alliances inside the cell on a genomic scale. "When you look inside a cell, it's not like you are looking at an isolated individual trapped on a desert island," he says. "It's more like a crowded party on New Year's Eve."
A party of proteins, that is. And understanding what those proteins are doing involves much more than simply reading the guest list. That's because most of the heavy lifting in the cell is performed not by individual proteins, but by multimeric protein complexes. "There is much more structural and functional organization in a cell than traditionally believed," says computationalist Sandor Vajda of Boston University, "and these are not simply pair-wise interactions." In some instances, as many as 50 proteins interact to form one large, well-organized machine.
[snip]
[last two paragraphs]
The computationalists themselves agree that, no matter how sophisticated their methodologies become, as Skolnick says, "at the end of the day you still need a carefully validated benchmark set where you really know that the interactions are there. Experiments are absolutely essential for that." That aside, he adds, "Computational methods are certainly no worse than experimental methods."
In silico or not, most protein biologists agree there is no single best tool for detecting protein interactions. Even with the whole arsenal at one's disposal, the new genome-wide approaches reveal only whether an interaction exists and then, between which proteins. They say nothing about what the interaction looks like nor how its thousands of atoms fit together, let alone whether it is biologically important. Yet it is precisely these questions that drug designers must answer if genomic-level proteomics are to lead to new drug development.
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