The Amaro Lab is broadly concerned with the development and application of state-of-the-art computational and theoretical techniques to investigate the structure, function, and dynamics of complex biological systems. At the interface of chemistry, biology, physics, and pharmacology, our research integrates both applied and basic science components, with goals to bridge the interface between basic and clinical research. Fundamental enzymological and drug discovery studies are tightly coupled to a wide range of biochemical and biophysical experiments that allow us to engage in dynamic and exciting collaborations with various experimental labs.
Our work is sponsored by grants from the Regents of the University of California, the National Institutes of Health, the National Science Foundation, and the Pacific Southwest Regional Center of Excellence.
Computational Translational Research
With petascale computing power on the immediate horizon and exascale computing not far behind, computational studies have the opportunity to make unprecedented contributions to drug discovery efforts. Large-scale simulations of increasingly realistic biological systems will allow us to investigate protein function and molecular recognition in atomic detail. These investigations will help drive discovery efforts and experimental work on these systems in collaboration with leading experimentalists. Our current investigations concern the neglected tropical diseases borne by the trypanosome organisms, potentially pandemic avian influenza, cancer, Chlamydia, and the cytochrome P450s.
Addressing Complexity in Molecular Recognition
The current model for computer-aided drug design is simply to take one or a few crystallographic structure(s) of a protein receptor and design a single molecule to block its activity. Though this model has had some success, more sophisticated drug discovery and design methodologies will significantly increase the chances of scientists being able to design more effective drugs faster. Our work in this area focuses primarily on three major goals: the incorporation of receptor flexibility, investigating mechanisms of drug and antiviral resistance, and disease network pharmacology.
With advances in the acquisition of biological structures, researchers can resolve near-atomic resolution structure of viral components. These studies give valuable information about what these proteins look like, which is important for understanding the infection process as well as to develop therapeutic options such as vaccines and drugs. However, because of experimental limitations, these datasets, though immensely informative, cannot give us a complete picture of these molecular machines. For example, mutations of various residues often need to be introduced to improve protein expression or to trap the molecule in a particular state. Regions that are highly dynamic are often removed, and, in addition, some biological components, such as lipid membranes and glycans, are difficult if not impossible to structurally resolve. Computational simulations, on the other hand, are not subject to the same limitations as experiment, and thus can be used to augment and extend experimental datasets. Biophysical molecular dynamics simulations are one such technique that allow researchers to restore the structures of experimentally determined biomolecular machines back to their original state, as well as add components that eluded experimental characterization. The Amaro lab uses such tools to explore the structure and dynamics of viruses and their interactions with the host cell at never-before-seen detail, ranging in scale from single protein investigations to whole virion studies.
Department of Chemistry and Biochemistry
University of California, San Diego
3234 Urey Hall, MC-0340
La Jolla, CA 92093-0340