Our research focuses on methodology
developments and biomedical applications at the interface of experimental
molecular biology and computational modeling to investigate 1) the effects of
co-aggregations of different Aβ peptides and fibril stabilities on Alzheimer’’s disease development and progress, 2) protein promiscuous activities and
exploited to engineer novo proteins for destructions of organophosphate
compounds, 3) roles of protein dynamics in molecular docking such that we could
design allosteric inhibitors that interfere with the post-translational modifications
of cellular proteins, 4) and to identify
new enzyme function.
Design small peptides: Alzheimer’s disease (AD), the leading cause of
dementia in Western societies, has an immense negative socio-economic impact.
In fact, the number of people living with AD is expected to quadruplicate by
the year 2050, from 32 million to 106-350 million worldwide. This potential for
increased incidence of AD introduces a critical need for medical breakthroughs
that prevent or slow the progression of the disease. To
this end, we aim to investigate 1) how sequence differences between interacting
peptides can impair oligomer formation; 2) how such mechanism can be exploited
for therapeutic purposes; and 3) how the stability of fibrils formed by
peptides may affect disease development/course.
Engineering bioscavengers/biomarkers: Organophosphate (OP) compounds have been extensively
used as pesticides and insecticides in agriculture, as a flame retardant in
plastics and rubbers, and even as a gasoline additive. Long term exposures to these OP compounds in
commercial products have been linked to several adverse health effects and
permanent damages to our ecosystem.
Enzymes have been used as therapeutics for decades due to their high
specificity, catalytic efficiency, and physiological preference. The search for
enzymes that act as OP scavengers has been an intense research topic. We aim to
characterize the reaction mechanisms of human serum paraoxonase and using
Rosetta Design to redesign PON1 to be used as safe and effective OP scavengers.
Design allosteric inhibitors: The interactions between ligand molecules and their
corresponding receptors are dynamic and complex. While ligand flexibility is
well accounted for, the effective inclusion of receptor flexibility remains a
pertinent goal in computer-aid drug design. We have recently developed new approach to
screen for allosteric inhibitors of the ubiquitin-conjugating enzymes,
E2. A detailed understanding of the
mechanisms that control binding of small molecules at the allosteric site is
therefore, important for therapeutic development candidates that target ubiquitylation,
in the middle of the pathway.
Identify new enzyme function: A grand
challenge in molecular biology is to assign the functions to all genes in
nature. The rapid advance in genome
sequence presents challenges for protein functional assignment. Structure
genomics initiatives contribute significantly toward this goal by producing
three-dimensional structures of many proteins.
However, the sequence-structure-function relationship is not always
linear (i.e., knowing the sequence and its structure does not guarantee knowing
a protein function). We have developed a
new computational scheme that leads identification of a new class of enzyme/protein
with novel activities.
Please contact us if you would like to collaborate or
join our research group. The UCSD directory contains our contact