• Research

  • Thermophilic adaptation is due to more favorable electrostatics

    Thermophilic adaptation is due to more favorable electrostatics

    I am carrying out my doctoral study under the supervision of Prof. Kingshuk Ghosh. The primary goal of my research is to use computational methods to understand fundamental principles of protein thermodynamics and ultimately advance quantitative models for protein stability. In particular, we are studying the origin of enhanced thermal tolerance in thermophilic proteins compared to their mesophilic homologues. We found the enhanced stability could be due to differences in the subtle charge patterning between orthologous pairs of thermophilic and mesophilic proteins. We use a novel scheme combining i) all-atom molecular dynamics (multi micro seconds long subject to careful convergence criteria) simulation of the folded state, and ii) all-atom Monte Carlo simulations for the unfolded state. These enable us to carefully investigate the role of the folded state dynamics and unfolded ensemble -- ignored in previous studies -- in thermophilic adaptation. Furthermore, the systematic approach allows us to separately compute the electrostatic contributions to the folded state, unfolded state interactions and solvation penalties. Applying this approach to multiple protein families, we gain insights to the role of different contributions of these effects to stability. This research has been published and a link is available in my publications tab.

    In addition, we are extending our computational approach to model effects of mutation to protein stability, a long-standing challenge in protein science. Our preliminary study shows the important role of folded state dynamics and unfolded state ensemble is important to correctly reproduce experimental results.


  • Intrinsically Disordered Proteins

    We are developing a sequence dependent theory to capture the conformational ensemble of intrinsically disordered proteins (IDPs). Our theory describes the complex coupling between sequence specificity, like charge decoration (the way the charges are arranged in the sequence), with solution conditions such as temperature. Due to the heteropolymeric nature of protein sequences, we notice that the internal distance profiles within the same protein (intra) can vary greatly, unlike homopolymers. We can also capture the differences in the coil-globule transitions among different proteins (inter) with similar sequences and charge compositions. Altering the charge decoration of a protein slightly, via post-translational modification (PTMs) or charge mutation, for example, may have a drastic impact on protein conformation dictating coil-globule transition. Not all PTM or charge mutation sites can produce a noticeable change, and our theory can capture the specific locations of these sites that have the most impact. Our theory is a high-throughput method for capturing the heterogeneity observed within a single protein and between multiple protein sequences. This will help in predicting the conformation and understanding the effect that altering sequence patterning may have on a specific IDP.

This portfolio last updated: 20-Aug-2020 10:20 AM