IIIT Hyderabad Publications |
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Network-based and Molecular Dynamics Analysis of Dynamic Allostery in ProteinsAuthor: Varun Naganathan Date: 2022-04-21 Report no: IIIT/TH/2022/64 Advisor:Nita Parekh,Marimuthu Krishnan AbstractAllostery is the process of regulation of a protein caused by the binding of a ligand at a distant region from the active site. It is one of the most widely 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. While traditional view of allostery considers large conformational and structural changes, the concept of dynamic allostery challenges this assumption, wherein ligandinduced 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 mechanism of dynamic allostery and identify residues involved in 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. The analysis involves using two popular approaches, Molecular dynamics simulations and network-based approach. We show that the combined MD and networkbased approaches together provide a better insight on possible allosteric communication pathways on ligand binding and also is able to improve the prediction of allosteric sites as compared to either of the methods individually. Additionally, in the extension of the webserver, NAPS, we developed interaction energy networks for the analysis of protein structures and support the analysis of MD trajectories such as construct and compare network-based features of protein structures from intermediate time-steps of the MD simulation. Full thesis: pdf Centre for Computational Natural Sciences and Bioinformatics |
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