Your mother always told you to do your geometry homework, and for scientists seeking new treatments for diseases like Parkinson's and Alzheimer's, this advice turns out to be right on the mark.
In the atomic-level landscape of proteins, shape determines the all-important function of these molecules of life. For example, when a protein molecule responsible for Parkinson's binds with the cell membrane, will a new drug candidate interrupt this interaction -- preventing disease progression and protecting the patient? It all depends on the precise geometry and energy of the protein structures.
Researcher Igor Tsigelny and colleagues at the San Diego Supercomputer Center (SDSC) and UC San Diego have developed a new tool known as MAPAS (Membrane-Associated Protein Assessments) which harnesses the power of supercomputers at SDSC and Argonne National Laboratory to study how proteins contact cell membranes. It turns out that this three-dimensional “virtual molecular world” is very good at letting researchers zoom in on key details of this all-important contact process, holding out the promise of new treatments for a wide range of devastating diseases, from Parkinson's and Alzheimer's to kidney disease and cancer.
“It's extremely important to explore the structural details of the zone where the protein contacts the membrane so that we can understand the molecular mechanisms of disease development,” said Tsigelny. “This knowledge gives crucial guidance in selecting which among many possible compounds are most likely to do well in tests to intervene in such protein-membrane interactions and help treat these diseases.”
The researchers describe the new MAPAS tool in the February 2008 (vol. 5 no. 2) online edition of Nature Methods. In addition to Tsigelny, the other authors, who are all at UCSD, include Yuriy Sharikov, Ross Walker, Jerry Greenberg, Valentina Kouznetsova, Sanjay Nigam, Mark Miller, and Eliezer Masliah.
In studying a protein, the traditional approach is to crystallize it and then illuminate it with X-rays, which yields information about its three-dimensional geometry, or “protein structure.” But this method has great difficulty in identifying the key parts of a protein that will participate in membrane contact.
“That's why it's very important to be able to predict these protein contact surfaces theoretically, using a computer program like we've developed,” said Tsigelny.
In making its predictions, MAPAS starts with a simple idea from geometry. Because an individual protein molecule is so much smaller than a round cell, the cell membrane looks like a flat surface as the protein approaches it -- just as the spherical earth appears flat to a person walking on it. This approach allows the researchers to more efficiently compute the structural information they are seeking.