Molecular Biology - The Scripps Research Institute

differed from the general folate template, and caused
inhibition when used in micromolar concentrations.
Currently, we are optimizing the lead candidates; our
goal is to obtain novel nonfolate inhibitors.
AutoDock is currently used in more than 3200
academic and commercial laboratories worldwide. We
continued development of AutoDock by testing a new
empirical free-energy force field. The force field incorporates
a charge-based model for evaluation of hydrophobicity
and an improved method for evaluating the
geometry of hydrogen bonding. The force field was
calibrated by using a set of 138 protein complexes of
known structure taken from the Ligand Protein Database
from the laboratory of C.L. Brooks, Department
of Molecular Biology. We anticipate that the revised
AutoDock, which incorporates this new force field and
methods for selective flexibility in the protein target, will
be released in 2005.
We also used AutoDock to predict intermolecular
interactions in several biological systems. In collaboration
with C.F. Barbas, Department of Molecular Biology,
we investigated the binding of peptides to the catalytic
aldolase antibody 93F3. To explore the large conformational
space available to these peptides, we used a
divide-and-conquer approach that separates the search
space into searchable blocks. In studies with G. Legge,
University of Texas, Austin, Texas, we explored the
interaction between the cytoplasmic tail of tissue factor
and the WW domain of proline isomerase PIN1,
focusing on the interaction of several key phosphoserine
residues.
FIGHTING DRUG RESISTANCE IN HIV DISEASE
We are continuing our work on inhibitors to fight
drug resistance in the treatment of AIDS (Fig. 4). In
collaboration with K.B. Sharpless and C.-H. Wong,
Department of Chemistry, we have focused on the
design of inhibitors that assemble within the active
Fig. 4. The predicted bound conformation of sanguinarine, a potential
lead compound for the development of novel HIV protease
inhibitors.
Published by TSRI Press ®. ©Copyright 2005,
The Scripps Research Institute. All rights reserved.
MOLECULAR BIOLOGY 2005 197
site of HIV protease. We showed that the triazole
formed in the click chemistry reaction is an effective
mimic for the peptide group in traditional inhibitors,
forming similar hydrogen-bonding interactions.
Currently, we are moving the FightAIDS@Home
system from an outside provider to a new server strategy
that will be implemented in the Molecular Graphics
Laboratory. FightAIDS@Home enlists the worldwide
community in a large computational effort to design
effective therapeutic agents to fight AIDS. Personal
computers are used in the program when the computers
are not in use by their owners, providing an enormous,
and largely untapped, computational resource.
The current goal is to identify inhibitors that are effective
against the wild-type virus and against common
mutant forms of the virus. The large computational
resources provided by FightAIDS@Home enables the
screening of large databases of compounds and use
of multiple mutant targets, allowing estimation of the
potential of a compound to remain effective when viral
mutations occur that cause resistance to drugs currently
used to treat HIV disease.
PREDICTING PROTEIN-PROTEIN INTERACTIONS
With the goal of creating a comprehensive tool for
predicting protein-protein interactions, we incorporated
both SurfDock and AutoDock into the Python programming
environment. SurfDock uses a variable-resolution
spherical harmonics representation to find candidate
orientations, and AutoDock is then used to explore local
atomic rearrangements at the interface. We tested the
method on a set of 59 protein-protein complexes of
known structure and optimized the level of smoothing
used in the spherical harmonics approximation of the
molecular surfaces. The results of the docking test
depended on the force field used to score possible orientations.
The best results were obtained with a residue-based
pair-wise potential of mean force.
VISUAL METHODS FROM ATOMS TO CELLS
Understanding structural molecular biology is essential
to foster progress and critical decision making among
students, policy makers, and the general public. In the
past year, we continued our longstanding commitment
to science education and outreach with a combination
of presentations, popular and professional illustrations
and animation, 3-dimensional tangible models, and a
presence on the Worldwide Web. In these projects, we
use the diverse visualization tools developed in the
Molecular Graphics Laboratory to disseminate results
that range from atomic structure to cellular function.