Author ORCID Identifier

0000-0002-4356-5349

Biosketch

Soundarya Priya Alexandar is a computational biologist specializing in multiscale molecular modeling and structure-based drug discovery. She earned her PhD from SASTRA Deemed University, where her research focused on understanding the molecular mechanisms of the mitotic kinesin EG5.

Her doctoral work provided detailed insights into the structural and dynamic behavior of EG5, a key protein involved in spindle assembly and chromosome segregation. She employed an integrative computational approach combining coarse grained dynamics, all-atom molecular dynamics simulations, protein-protein docking, and network analysis to study how nucleotide binding and allosteric inhibitors regulate EG5 function.

Her research identified clear mechanistic differences between allosteric site I and site II inhibition. Site I inhibitors were found to restrict conformational flexibility, while site II inhibitors disrupted key functional regions and weakened microtubule interactions. She also demonstrated that dual site inhibition produces synergistic effects on structural stability and residue communication networks.

Her work contributes to advancing targeted anti-mitotic drug design and supports the development of more selective therapeutic strategies with reduced off target effects.

Date of Award

23-9-2025

Document Type

Thesis

School

School of Chemical & Biotechnology

Programme

Ph.D.-Doctoral of Philosophy

First Advisor

Dr.U.Venkatasubramanian

Keywords

Kinesins, Allosteric Inhibition Mechanisms, Multiscale modelling, EG5, Cancer

Abstract

The mitotic kinesin EG5 is essential for spindle bipolarity and accurate chromosome segregation during cell division, making it a validated anti-cancer target. Unlike conventional microtubule-targeting agents, EG5 inhibitors offer mitosis-specific action, reducing neurotoxicity. Although inhibitors targeting EG5’s allosteric site-I have been extensively studied, mechanistic insights into inhibition at site-II, and their combined effects, remain underexplored. This thesis systematically investigates the structural and dynamic mechanisms underlying EG5 function and its inhibition using an integrative computational approach.

Conformational analysis, coarse-grained dynamics, all-atom molecular dynamics simulations, and protein network analysis were performed on EG5 motor domain structures and EG5-microtubule complexes. Results show that ATP binding stabilizes EG5 and enhances microtubule affinity by promoting conformational locking. Inhibitors at site-I primarily restrict conformational flexibility and stabilize inactive states, while site-II inhibitors induce destabilization of functional regions critical for nucleotide binding and microtubule interaction. Dual-site inhibitors exert a synergistic effect, simultaneously restricting conformational mobility and disrupting residue communication networks. Protein-protein docking revealed that ATP binding strengthens EG5’s interaction with β tubulin, while site-II inhibitors significantly weaken these interactions.

Network analyses further uncovered that inhibitor binding remodels the internal allosteric communication within EG5, offering new insights into the molecular basis of inhibition. This study provides the first comparative analysis of site-I and site-II inhibition mechanisms in EG5, alongside frameworks for understanding and investigating allosteric regulation. The findings advance fundamental knowledge in mitotic kinesin regulation and offer broader implications for targeted drug design against dynamic motor proteins.

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