Molecular structure and dynamics underly all biological processes. Most research in biomedical fields is directly or indirectly associated with molecular behavior. In the field of biochemistry, experimental approaches have been directly targeting these molecular properties, albeit within a specific “window” of observable length and time scales. Computational approaches can offer much wider windows, but present only hypotheses about the system rather than “real” observables. Integrated computational and experimental approaches, therefore, present unparalleled strategies for exploring biological systems, a philosophy that has guided us in my laboratory.

Perhaps the most outstanding challenge in computational biology is sampling of molecular conformational states. Most research in our laboratory has been dedicated to solving this critical problem. We have been pursuing this goal by developing rapid discrete molecular dynamics simulations, novel and unique in the level of accuracy molecular docking algorithm that we have already used to find novel lead compounds to treat CF and reduce chronic and acute pain (in both cases these compounds are been pursued by biotech companies). We are currently pursuing understanding of other human diseases and developing novel pharmaceutical strategies to combat them, and actually searching for compounds using a combination of virtual drug screening and experiment. Application of these tools also allows rational design of proteins that can control other proteins in living cells and organisms. These tools are becoming invaluable resources that enable decoupling cellular networks, as well understanding the impact of a specific protein on the phenotype of an organism. Below, we describe ongoing projects in the lab.

METHODOLOGIES

Molecular Modeling and Simulations
Drug Discovery
Protein Design of Tools for Sensing and Controlling Proteins
RNA structure and dynamics

DISEASE ETIOLOGY

Protein misfolding is increasingly implicated in many diverse human diseases, including amyotrophic lateral sclerosis (ALS), cystic fibrosis (CF), anemia, phenylketonuria, hyperammonemia, Lesch-Nyhman syndrome, Fabry disease, and others. Protein misfolding results either in loss of function (e.g. in CF) or in toxic gain of function (e.g. in ALS). The fundamental significance of protein misfolding is difficult to over-estimate, yet little is known about molecular mechanisms that result in protein misfolding at the atomic level. Understanding protein misfolding and aggregation will greatly impact modern medicine and biology, and will allow development of novel pharmaceutical strategies.

We use a multidisciplinary approach that uniquely combines biophysics, biochemistry, and structural and computational biology to uncover mechanisms of protein misfolding and aggregation. We then use our knowledge of these mechanisms to uncover etiologies of human disease and develop novel therapeutic strategies. We study a broad range of diseases associated with protein misfolding, but focus on two very distinct ones: ALS and CF, described below.

Amyotrophic Lateral Sclerosis
Cystic Fibrosis

PROTEIN-BASED THERAPEUTICS AND NANOMEDICINE

Organophosphate Scavenging
HIV vaccine
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