Structure of the trp cage protein
Realizing the Promise of "Post-Genomic
Medicine"
The sequencing of the human genome prompted a titanic
eruption of enthusiasm for the new future of medicine,
based on the development of drugs targeted to the genes and
protein products whose dysfunction can be implicated in
human disease. Then the daunting work began of pursuing the
connections among human disease, the genome's three billion
base pairs and the hundred thousand proteins they generate
in the course of operating and maintaining the human body:
most of that trail still lies ahead. Since form follows
function, a threshold issue is to determine the shapes of
proteins, whose constituent chains of amino acids owe their
sequence to their genetic encoding but their functionality
to the three-dimensional structures they assume through a
process of folding.
The best available experimental methods, NMR and x-ray
crystallography, are exceedingly slow and labor-intensive
for seeing protein shapes. Efforts to develop a new
technique based on the growing power of computing
technology and advances in modeling had been frustrated
until a group of researchers, led by Carlos Simmerling, a
member of the Department of Chemistry and the Center for
Structural Biology, achieved the critical initial step
toward this grail. The group succeeded for the first time
in correctly predicting a protein's actual structure at the
atomic level through computer simulation, based solely on
the protein's gene sequence and the attraction and
repulsion tendencies of its constituent amino acids. Even
though the protein was relatively small, originally
isolated as a fragment of a larger protein, the researchers
had to build their own supercomputer with hundreds of PCs,
and run a long and complicated computer program that they
wrote to simulate the physics of the molecules, in order to
achieve their successful results.
The results were confirmed by actual measurements on the
protein, made through nuclear magnetic resonance
spectroscopy, by a team at the University of Washington.
News of the breakthrough, which points the way toward
modeling much larger and more complex proteins, which can
be composed of much longer amino acid chains, appeared
around the world in languages ranging from Chinese and
Korean to Russian, Danish and Basque. The group's report
was published in the Journal of the American Chemical
Society and may be found at-- http://pubs3.acs.org/acs/journals/doilookup?in_doi=10.1021/ja0273851