I work on many different problems in the interface of physics and biology: the common theme running through my research is Non-equilibrium self-assembly in living systems

Organization of chromatin and the fate of a cell

DNA is a very long ribbon-like polymer that contains the genetic code. Even though different celltypes in our body (skin cells, muscle cells, brain cells, etc.) have exactly the same DNA, these cells function very differently. How is this achieved is not well understood. We now know that the fate of a cell is not just decided by the sequence of the DNA but also by the “state” of its chromatin. Chromatin is a 3-dimensional active assembly of DNA bound by many proteins (a set of bio-polymer molecules). Chromatin can be assembled in multiple ways and our skin cells have a different chromosome organization compared to our brain cells and that eventually results in different function. In other words, regulating its organization, different parts of the DNA (genes) are made inaccessible (off) and accessible (on) leading to different cell types and functions. In our lab, we do theoretical/computational studies to investigate different types of plausible chromatin organizations and their implications.

At the primary level, DNA polymer is wrapped around many ball-like proteins (known as nucleosomes) to assemble chromatin in the form a “string of beads”. The precise positioning of nucleosomes in space and time is crucial as it can regulate the accessibility of DNA-binding proteins to the genetic code. Using computer simulations and theoretical tools from physics and chemistry, we investigate the following questions: Given the experimentally known positioning of these nucleosome beads, can we derive a set of rules obeyed by the self-assembling nucleosome beads How do the positioning and dynamics of these nucleosomes affect the switching ON and OFF of genes? In other words, how do nucleosomes take part in the “decision making” process in a cell? How do nucleosomes affect the 3-dimensional organization of the genome?

Self-assembly of proteins

Self-assembly of bio-macromolecules into higher-order structures is a commonly observed feature in biology. Protein self-assembly in particular is associated with a wide range of functions including cell division and cell motility and diseases such as Alzheimers’ and Parkinsons’. The forces generated during the growth of native self-assemblies such as actin and microtubules is vital for cellular function. The generation of forces is achieved by a reversible polymerization of the constituent monomers (tubulin and actin monomers). On the other hand, aberrant self-assembly of proteins due to incorrect folding or changes in solution conditions could lead to the formation of beta-sheet rich filaments known as amyloids which could result in cell death, like in case of neurodegenerative diseases. However, similar ordered structures have also been known to perform useful functions such as reversible hormone storage, scaffold for cell growth etc.

In our group, we describe the dynamics and structural features of these molecular self-assemblies using fundamental physical principles. We provide a theoretical description of the self-assembly process using key chemical events such as polymerisation, depolymerisation, chemical modifications (GTP hydrolysis in microtubules) and structural transitions (coil to beta-sheet conversion in amyloid monomers).  We identify various rate regimes under which the typical kinetic signatures in various self-assembling filaments (sigmoidal growth kinetics in amyloids, dynamic instability in microtubules etc) are encountered.  Also, these simulations help us explore the various ‘kinetic phases’ that would result upon altering the rates that govern self-assembly. For instance, under which rate regime would one observe an amyloid-like assembly as opposed to a globular aggregated structure? Similarly, what are the factors that dictate catastrophe frequencies in microtubules? We use kinetic Monte carlo simulations and analytical theory to answer these questions. Another research focus of our group is to probe various structural features of these self-assemblies. For e.g, what are the physical factors governing the nature of the aggregate? Overall, the emphasis is on studing the kinetic and structural aspects of protein self-assemblies using computer simulations and theory.