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V Naganathan – Molecular Dynamics Analysis

Varun Naganathan received his MS Dual Degree in  Computational Natural Sciences (CNS). His research work was supervised by Dr. Nita Parekh. Here’s a summary of his research work on Network-based and Molecular Dynamics Analysis of Dynamic Allostery in Proteins:

Allostery is the process of regulation of a protein caused by the binding of a ligand at a distant region from the active site. Its one of the most vastly studied properties of proteins and biological systems. Ligand binding at allosteric sites lead to a conformational change in the protein, propagated via changes in protein dynamics that alter the capability of the protein to bind to ligands or molecules at active sites. Allostery is required by biological systems to carry out several crucial functions like hormone binding to receptors, protein regulation to name a few. Understanding the underlying allosteric signaling mechanism on ligand binding has immense applications in the field of drug design, It is also applicable to understand the way diseases operate within our bodies and hence developing more effective and selective drugs for the same as well as understanding biological systems better. While traditional models of allostery have seen to associate allostery accompanied by conformational and structural changes, the concept of dynamic allostery challenges this assumption. The concept of allostery without conformational changes has been highlighted for the PDZ system [4] whereby ligand-induced changes in protein dynamics could produce allosteric communication between distinct binding sites, even in the absence of macromolecular conformational changes.

In this thesis, we have considered PDZ domain of protein PSD-95 as our model system to understand the allosteric mechanism associated with dynamic allostery. PDZ domains are evolutionary conserved protein-protein interaction modules associated with cellular signaling and are implicated in the localization of membrane receptors and ion channels. We approach to understand the allosteric mechanism through the two popular classes of methods – Molecular dynamics and network-based methods. We compare and contrast both these methods to identify allosteric sites in the PDZ system and see how energetics provide a good means to uncover the allosteric mechanism. We then combine MD and network based methods to better inspect the conformational landscape of the protein during ligand binding and find a combination of the two to identify all previously known allosteric sites as well as provide us insights on possible allosteric communication pathways.

Additionally, we applied the above combination of Md trajectories and network approaches into a web server – NAPS2. We extended the previous existing NAPS server to now additionally plot interaction energy networks. We provided support to upload MD trajectories and plot intermediate networks for the trajectory snapshots and perform various analysis on intermediate snapshot networks including node/edge centrality, shortest paths, k-clique and graph spectral analyses. We also added functionalities to compare network properties across two intermediate timesteps of the MD trajectory to better contrast and compare the dynamical changes in the protein structure. Each of the above results can also be downloaded in suitable format.