It’s All About Geometry: Protein Contact Surfaces
Hold Key to Cures
Supercomputer Powers Tool to Reveal Hidden
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.
January 31, 2008. Source:
University of California,
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
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
“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
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
“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
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
The MAPAS tool takes as a starting point a protein’s known three-dimensional
shape, and then applies a set of scoring methods based on comprehensive Steered
Molecular Dynamics calculations to predict whether this protein structure can
form strong contacts with the cell membrane. If so, MAPAS goes on to identify
all the flat faces or planes that make up this protein. It is these planar
protein surfaces that can attach to the cell membrane, and MAPAS predicts which
of these regions are most likely to bind to the membrane, based on specific
protein contacts with the lipids or fats that make up the membrane.
The team has validated the performance of MAPAS by confirming that it correctly
models a number of membrane-contacting proteins that are already known.
The powerful MAPAS program with its virtual protein world is already providing
important benefits in both extending basic scientific understanding of proteins
and fighting disease.
“For example, without the MAPAS program we wouldn’t have been able to develop
the important new model we found for Parkinson’s disease,” Tsigelny explained.
He and his colleagues have already published an important advance in
understanding this disease, based on computations using MAPAS. These new
insights can in turn open important avenues for developing new treatments.
Added Tsigelny, “We’re also currently using MAPAS to study Alzheimer's disease
mechanisms as well as molecular models of the processes involved in kidney
disease and some cancers.”
The importance of the work has been recognized by a prestigious Department of
Energy (DOE) Innovative and Novel Computational Impact on Theory and Experiment
(INCITE) award of 1.2 million processor hours, which will allow the team to run
their programs on a supercomputer at Argonne National Laboratory and extend
their research on Parkinson’s disease.
The researchers are also working to create a supercomputer-powered system that
unites multiple programs, including MAPAS with multiple data sources, to carry
out comprehensive studies of the mechanisms in diseases involving
Source: University of California, San Diego