The main goal of our research is to develop and utilize computational methods based on statistical mechanics and classical simulations to address molecular-level phenomena relevant to biology, medicine, and nanotechnology. Our research interests fall along three main themes: (1) DNA organization and regulation, (2) Single-molecule mechanics, and (3) Functional bio and nanomaterials. Below we describe specific research projects that we are currently working on:

Chromatin structure and dynamics under forces

In eukaryotic organisms, DNA is present in the form of a 30-nm chromatin fiber made up of repeating units called nucleosomes. Each nucleosome consists of 1.7 turns of DNA wrapped around an octamer of histone proteins H2A, H2B, H3, and H4. Significant progress has been made in determining the detailed structure of chromatin under different salt conditions and in the presence of different architectural proteins. However, little is known about how chromatin behaves under the myriad forces accompanying biochemical processes like DNA transcription, replication, repair, and recombination. Our laboratory is currently developing mesoscopic models of chromatin and simulating them under different kinds of external forces to provide fundamental insights into the dynamics of chromatin in vivo. Our laboratory is also collaborating with the groups of Dr. James Kadonaga (UCSD Biology) and Dr. Doug Smith (UCSD Physics) on the single molecule biophysics of chromatin.

Role of histone modifications in gene regulation
It has only become clear in the last decade that a complex interplay of posttranslational histone chemical modifications regulate chromatin structure and dynamics to in turn regulate gene expression. For example, K16 acetylation on the histone tail H4 is strongly correlated with gene transcription, while other modifications promote silencing of genes. However, our current understanding on how these modifications act individually or in tandem to alter the physical state of chromatin remains very qualitative and new approaches are needed to shed light into the mechanisms of chromatin regulation. We are currently using a variety of computational methods such as molecular dynamics simulations and molecular docking calculations to elucidate the microscopic mechanisms by which histone biochemical modifications, especially those relating to cancer, alter chromatin structure to control gene expression.

Analysis of single-molecule force spectroscopy data

Applying controlled forces to single molecules or molecular assemblies by means of micromanipulation techniques like optical tweezers provides quantitative information on the underlying energy landscape and the kinetics. The "nonequilibrium" response of the system to these forces in terms of force-extension curves, distribution of rupture forces or rupture times, and average rupture forces is recorded and analyzed using various analytical models to extract "equilibrium" information about the system such as the intrinsic free energy barrier and the transition frequency of the molecule between different macroscopic states of the molecule. We are currently developing such analytical models incorporating the effects of the pulling device and handles for extracting such thermodynamic and kinetic information in a more reliable manner.

Computational design of catalytic RNAs
RNAs represent a very versatile class of biomolecules. In particular, some RNA molecules, known as ribozymes possess catalytic activities. For example, the hammerhead ribozyme can catalyze its own cleavage, while group I and group II introns can catalyze their own splicing reaction. These RNA molecules have been engineered to operate on target substrates, rather than on themselves, thus yielding trans-cleaving and trans-splicing ribozymes. Such modified ribozymes may be useful for therapeutic application. We are interested in developing computational models that can predict all aspects of catalytic RNA molecules, from target accessibility to reaction efficiency, thus accelerating the process of designing ribozymes optimized to achieve specific therapeutic effects, such as gene knock-down and gene repair. This work is being carried out in collaboration with Dr. Muller's laboratory at the UCSD Chemistry department.

Self-assembly of polymer-grafted nanoparticles

Nanoparticles grafted with charged polymers exhibit unique properties that could have many applications in paint and oil industry. One unique property that these systems exhibit is a salt-dependent electrostatic attraction between nanoparticles carrying the same overall charge that defies the common notion "like charges always repel each other". Our group is developing computational methods to fundamentally understand the origin of this attractive interactions in terms of enthalpic and entropic factors at different conditions of interest. We are also developing strategies for manipulating the interactions between shaped nanoparticles involving grafting of polymer chains to direct their assembly into useful nanostructured materials, especially for plasmonic applications. For this project, we are collaborating with the group of Dr. Andrea Tao.

Smart biomimicking materials
We have a strong ongoing collaboration with the group of Dr. Shyni Varghese on the development of novel biomimicking materials. In one project, our collaborators have developed electric-field responsive hydrogels that could bend in either direction, based on our theoretical modeling of osmotic pressure changes at the gel-solution interface. Such bending gels could serve as unique tissue culture systems capable of supplying mechanical, chemical, and electrical cues simulataneously to the cells. In another project, our collaborators have developed rapid, self-healing hydrogels, whereby two gels can stick to each other and heal in a matter of seconds within an acidic medium. The design of these hydrogels was facilitated by simulations performed in our group that delineated the conformation of the dangling sidechains of the hydrogel network and the mechanism by which they mediate healing.

Design of energy dissipating elastomers

This project is in close collaboration with the groups of Dr. Sia Nemat-Nasser at UC San Diego and Dr. Zhibin Guan at UC Irivine. Our aim is to develop new and improved elastomeric composite materials for mitigating and/or redirecting blast-induced stress waves over a range of frequencies and energies. Our group is using a range of computational methods to provide molecular-level insights into energy dissipation and redirection within polymer nanocomposites as a function of polymer architecture and nanoparticle composition. Some of our ongoing work includes developing high-resolution models of polyurea, the polymer currently used for the above application, and examining its viscoelastic properties and shock response in order to dissect the molecular origins of its superior dissipative properties.

Other projects

We are also embarking on several exciting projects on modeling the structure and dynamics of chromosomes in collaboration with Dr. Cornelis Murre, and on the modeling of nucleosome remodeling via ATP-dependent enzymes in collaboration with Dr. James Kadonaga