Cellular Compartments

We use computational tools to understand function-folding-stability trade-offs in proteins. The amino-acid sequence of a protein includes residues which are important for function and defines an energy landscape on which both protein folding and functional dynamics occur. Thus, both functional residues and functional dynamics leave “footprints” on the folding landscape of the protein. We use structure-based models and molecular dynamics simulations to understand the folding of proteins in order to predict the effects of protein function on folding. These effects are diverse and we have found that functional residues can make a protein fold faster (in hisactophilin and interleukin-33), slower (in interleukin-1β) and change folding routes (RNase-H and interleukin-1β). Our folding simulations provide key insights into the function of a protein not available otherwise. These insights will aid the mutational modulation of function and in turn protein design.

Since the cell surface has to manage and process a large spectrum of information from the outside into the interior of the cell, its composition must be organized and regulated over different spatial and temporal scales. A great challenge in cell biology is to understand the physico-chemical principles that underly this regulatable organization. We have been studying the local control of composition and shape of the cell surface as an active composite of a multicomponent, asymmetric cell membrane coupled to a cortical layer of actin and myosin using a variety of theoretical and experimental techniques. This has implications for cellular processes such as molecular clustering, cell surface signaling, molecular sorting and endocytosis.

The remodeling and transport of organelles and vesicles are also active processes. We are interested in the active dynamics of intracellular trafficking in the endosomal and secretory pathaways, which involves the interplay between organelle (membrane) shape, composition and activity of fission, fusion and transport. In this context, we are studying the remodeling dynamics of mitochondria and Golgi, and the biogenesis of the Golgi cisternae, using the analytic and numerical techniques of nonequilibrium statistical physics and soft matter. More recently we have formulated an optimization strategy associated with cell-type identification and discrimination, involving the interplay between sequential enzymatic processing of glycans and the dynamics of trafficking across cisternae.

We have shown that mechanically, the cell nucleus is described as an active polymeric gel. This has implications for the spatiotemporal patterning of chromatin within the nucleus and in-vivo interphase chromatin folding at large scales. Our results lead us to conjecture that the chromatin conformation resulting from this active folding optimizes information storage by co-locating gene loci which share transcription resources. In addition, we are interested in understanding how mechanical and chemical signals propagate from the cell surface to the nucleus to affect nuclear shape changes, chromatin organization and gene expression, using an active hydrodynamics formalism.

The patterning and remodeling dynamics in tissues is driven by an interplay between active mechanical stresses from actomyosin, cell adhesion forces from cadherin and a multiplicity of signaling pathways. We have been studying the dynamics of cell intercalation during germ band elongation in the drosophila wing imaginal disc, driven by actomyosin pulsation and flow using an active elastomer model. In addition, we have been interested in the active dynamics of dorsal closure and the scale invariance of developmental patterning in tissues.