Fractal Assembly of Citrate Synthase: Scaling the Growth, Entropy and Stability

Manasvini, S (2025) Fractal Assembly of Citrate Synthase: Scaling the Growth, Entropy and Stability. Masters thesis, Indian Institute of Science Education and Research Kolkata.

Text (MS Dissertation of S Manasvini (20MS077)) 20MS077_Thesis_file.pdf - Submitted Version Restricted to Repository staff only Download (45MB)

Abstract

This study explores protein self-assembly into higher-order structures. In this thesis, we investigate the geometric, energetic, and dynamical principles underlying the hierarchical self-assembly of Citrate Synthase oligomers, ranging from dimers to large, fractal-like multimers. Using molecular dynamics simulations and custom structural analyses, we quantify how modular interfaces mediated by key residues such as Arg369-Glu6 stabilize assemblies across scales. We explore scaling behavior through structural parameters such as radius of gyration, solvent accessible surface area, and interfacial contacts. The scaling exponent v derived from Rg ∼ Nv corresponds to a fractal dimension α ≈ 1.5, situating these assemblies between extended configurations and compact globules. We also analyze void formation using a custom algorithm based on voxelization and marching cubes algoriothm, revealing unoccupied spaces that cannot be detected by conventional cavity tools. Dynamic cross-correlation matrices and root mean square fluctuation (RMSF) profiles uncover the emergence of collective motion, with increased correlation in symmetric assemblies such as the hexamer and 18-mer, and higher fluctuations in intermediate, less stable forms like the 4-mer and 12-mer. Thermodynamic signatures, such as specific heat derived from energy fluctuations, further depict scaling relationship. Overall, this work provides a framework to understand how geometric symmetry, and dynamic coupling contribute to stability in protein assemblies. It also highlights the potential of fractal organization as a design principle in biological self-assembly.

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