April - BioGeometry Project

BioGeometry NEWS
April
2003
biogeometry.cs.duke.edu
Announcements
BioGeometry Meeting
Annual Report
The next ITR BioGeometry meeting
will take place at Stanford University
on Thursday-Friday, June 5-6, 2003.
It’s being organized by Michael
Levitt. The schedule and other details will be available soon at http://
biogeometry.cs.duke.edu/meetings/
ITR/03jun.
Time is approaching to prepare the Year 3 annual report for submission to the
NSF. Here’s the schedule:
• May 8: An email announcement will be sent to PIs requesting submissions,
and providing details on reporting requirements
• May 22: Deadline for submitting information
• Beginning May 22: Draft report will be prepared
• June 5-6: At the ITR meeting at Stanford, PIs will review and edit the draft
• Soon after June 6: Final editing, final review by PIs, submission to NSF
The frequency of
BioGeometry
meetings is increasing from annual
to biannual, and this is the first of the
biannual meetings.
Please begin thinking about material you might contribute for the report,
including participants, publications, software, research projects and results,
educational courses and materials, collegial and educational outreach, and
outreach to under-represented groups. Also think about inter-disciplinary and
inter-institutional collaborative accomplishments.
Student Profile: Loren Looger
L
oren Looger is a fourth
year PhD student at Duke
University, working under the
supervision of PI Homme Hellinga
in the Department of Biochemistry.
Loren did his undergraduate work
at Stanford where he received his
BS in Chemistry. He then obtained
a Masters in Mathematics at
Stanford. After a one-year stint in
the PhD program in Mathematics at
UC Berkeley, Loren decided that he
did not want to leave experimental
science and joined the Biochemistry
program at Duke instead. He will
graduate this summer.
Loren has been working on a
combined
computational
and
experimental approach to the design
of protein function. He has focused
on developing and experimentally
validating methods for the redesign
of receptor proteins. This work has
proven to be very successful and
will be reported in a paper to appear
in the May 8 issue of Nature. The
essential idea of the receptor design
algorithm is illustrated in Figure 1.
We start with a receptor of known
three-dimensional structure with a
bound ligand (Fig. 1a). The
amino acid residues that
interact with the wild-type
ligand are replaced with
poly-alanine (red lines in
Fig. 1b), thereby creating a
cavity. Within this cavity, an
ensemble of the new ligand
is docked, representing
the allowed rotations and
translations within the cavity.
This ensemble is constrained
by a convex polytope that
describes the approximate
location of the original ligand.
The algorithm then identifies the
“best” docked ligand and amino acid
sequence that binds that ligand (Fig.
1c), using a version of the Dead-end
Elimination algorithm developed
by Loren to solve the immense
combinatorial complexity that arises
in this minimization problem. Using
this algorithm a series of bacterial
receptors that normally bind sugars
or amino acids was converted into
receptors for the explosive TNT, an
analog of the nerve agent soman,
the ground water pollutant MTBE (an
anti-knock gasoline additive), various
neurotransmitters and metabolites.
All of these were experimentally
validated by Loren and his fellow
graduate students and postdocs in
the laboratory.
Besides Loren’s ability to solve
difficult computational problems, he
is also a very good experimentalist
who can build genes, and produce
and study mutant proteins. It is this
seamless integration of the worlds
of computation and experimental
biology that allows interesting and
difficult problems to be solved.
- Profile by Homme Hellinga
Figure 1. Steps in the design of a receptor for serotonin. On the left we see the original binding site with a sugar
bound by the wild-type protein (the serotonin is indicated as a ghostly image). On the right we see the redesigned
site with serotonin bound (now the sugar is shown as a ghost). In the middle we see an intermediate step in which
docking of serotonin is explored.
BioGeometry News is the monthly newsletter of the BioGeometry project.
For more information, please visit http://biogeometry.cs.duke.edu/newsletter.
The project is funded by the National Science Foundation under grant CCR-00-86013.