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.

1)    Design small peptides:  Alzheimers 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 Aβ peptides can impair oligomer formation; 2) how such mechanism can be exploited for therapeutic purposes; and 3) how the stability of fibrils formed by different Aβ peptides may affect disease development/course.

2)    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.

3)    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.

4)    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 information.

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