Research

Current Research Topics

Molecular Mechanism of Calcium Signalling and Engineering Proteins to Control Signal Transduction: Toward Understanding Calcium Signalling Pathways

Calcium ions (Ca²⁺) are involved in diverse biological processes by activating regulatory proteins such as calmodulin. The challenge in studying the binding process includes inaccuracy in the Ca²⁺ forcefield, sampling of conformational space and high computational costs. We looked at the origin of the differential binding affinity of Ca²⁺ binding to different sites of calmodulin and developed a structure-based predictive model for binding affinity. In collaboration with experimentalists, we are applying quantum mechanics, statistical physics, and machine learning methods to elucidate how the biophysical properties of Ca²⁺ and proteins shape function at a cellular level. We are interested in rationalising and predicting Ca²⁺ affinity and engineering calcium-binding proteins to enhance the signalling process.

DNA-ION Interaction

The storage, transmission, processing, and control of genetic information rely heavily on nucleic acids, which also act as catalysts and mechanochemical switches as well as carriers of the genetic code. Large interaction energies are provided by interactions between nucleic acid and ions. Therefore, these interactions are an essential aspect of a comprehensive explanation of the folding of functional DNAs and RNAs, of interactions of nucleic acids with ligands and macromolecule partners, and of the activity of RNAs and RNA-protein complexes and machines. Thermodynamic and mathematical frameworks for ion-nucleic acid interactions have been presented in various ways. With the help of recent experimental advances, it is now possible to describe the crucial aspects of the ion atmosphere and how they affect nucleic acids and their interactions in a way that is both more logical and scientifically supported.

Implicit Solvation with Physical and Structural Properties: Analytical Modelling of Hydration Thermodynamics of Small Organic Molecules

Water is present in almost all chemical and biological phenomena. To study the biomolecules in water or water itself, two main approaches are used to model water: explicit and implicit. The explicit models are physically accurate but they trade off the speed, while implicit models have a speed advantage over physicality. We are trying to explore a third option that makes a different trade-off. We are developing an analytical model to calculate hydration thermodynamic properties using the statistical mechanical-based analytical variant of the MB water model. Here, we treat the solvation shell as having tetrahedral waters, treated through statistical mechanical averaging and combined with a surface physics term.

Protein Unfolding

Protein unfolds under pressure, typically above 3 kbar. Why do proteins denature at high pressure? Despite decades of research, the mechanism of protein denaturation under pressure is still a hotly debated topic. Several views emerge from various experiments and computer simulations. The most widely accepted reason for unfolding is considered to be the penetration of water into the protein interior upon application of pressure, leading to unfolding. Applying high pressure restricts the translational and orientational movement of the water molecules; however, water insertion may relax the above two motions outside the protein molecule. Whether enthalpy or entropy is the main driver of protein unfolding is a key issue that we are trying to explore using computer simulations.

Some of the Previous Research Topics

Development of enhanced Monte Carlo simulation techniques to explore the energy landscape of water clusters and biomolecules

We have developed an efficient Monte-Carlo-based method, Temperature Basin Paving, for the exploration of complex energy landscapes. We have successfully applied this method to different sizes of water clusters and small RNA hairpins and continuously optimizing this method for complex systems.

Properties of RNA with non-Watson-Crick base pair

Non-Watson-Crick base pairs are the basic necessity for different three-dimensional folds of RNAs and the activity of different Ribozymes. These folds make the interaction of RNAs with proteins, other molecules, and ions possible. Non-Watson-Crick base pairs always need some external factors like metal ions, other ribosomal strand or proteins for stabilization. In the current work, we are analyzing different aspects of the stabilization mechanism of non-Watson-Crick base pairs by these external factors.

Development of a model of the cytoplasm of a bacterial cell and understanding of diffusion and hydrodynamics

In this work, we have developed a computational model of E. coli cytoplasm to study the diffusive motion of proteins inside the cell. The model contains the most abundant proteins present E. coli cytoplasm that has been coarse-grained in the form of a collection of spheres. The presence of a large number of particles provides large volume exclusion and hydrodynamic interactions which in turn affect the diffusivity of proteins inside the cell. In this work, we are trying to determine the effect of crowding and hydrodynamic interactions on the diffusive motion of proteins.

Development of Random Walk model to study anomalous diffusion

Subdiffusion is ubiquitous in a crowded heterogeneous environment, but the exact cause of subdiffusion is still debatable. In this work, we are trying to understand the cause of subdiffusion in a crowded and heterogeneous environment using random walk models. By developing different models, we are working to understand the cause of transient and pure anomalous diffusion with constant diffusion exponent at all time scales.

Effect of molecular crowding on biomolecular systems

Living cells have vast varieties of molecules like nucleic acid, protein, small messenger molecules, osmolytes, carbohydrates, and insoluble molecules. These molecules are known to occupy a significant fraction of cellular volume(20-40%) and are referred to as molecular crowders. Molecular crowding has large quantitative effects on the structure, thermodynamics, and function of nucleic acids and proteins by excluding volume and interacting with them. It has been shown that molecular crowding affects properties of nucleic acid like melting temperature, hybridization, structural preference, diffusion, etc. In this work, we are trying to understand the structural, hydration, and thermodynamics of the canonical form of DNA in a crowded environment. One of the ways to understand DNA stability is to understand the thermodynamics of its hydration, which we are currently focused to look at.

Effect of salt electrostatics on like-charged protein-protein binding

Here, we are trying to explore the effect of salt ions on the like charged protein-protein binding. How does salt ion concentration in the system affects the like-charged protein-protein binding and what roles are played by salt ions near the binding interface which determines the free energy change of complex formation, are the questions we are trying to address.