Integrating Multi-scale Modeling and Simulation to Investigate Mesoscale Structural Dynamics of Biopolymers

Sinha, Anushree (2026) Integrating Multi-scale Modeling and Simulation to Investigate Mesoscale Structural Dynamics of Biopolymers. PhD thesis, Indian Institute of Science Education and Research Kolkata.

Text (PhD thesis of Anushree Sinha (20RS140)) 20RS140.pdf - Submitted Version Restricted to Repository staff only Download (14MB)

Abstract

Large biomolecular systems undergo conformational transitions on millisecond-to-second timescales, posing major challenges for classical all-atom molecular dynamics simulations. To overcome these limitations, this thesis develops and employs multiscale simulation strategies to probe long-time, large-scale dynamics in multidomain proteins and RNA systems. First, a symmetry-informed coarse-grained (CG) structure-based model (SBM), constructed using Cryo-EM data, is employed to investigate the prefusion dynamics of trimeric SARS-CoV-2 spike protein, focusing on the Alpha (B.1.1.7) variant. The model captures the characteristic up–down transitions of the receptor-binding domains (RBDs), reproducing large-scale motions essential for receptor accessibility and functional activation. This analysis reveals how evolutionarily conserved missense mutations modify two distal intrinsically disordered regions (the 630 loop and FPPR loop), which together act as a cervical collar that allosterically stabilizes functionally relevant spike-head conformations. Extending this framework to later variants of concern, Delta (B.1.617) and Omicron (BA.1), graph-theoretic network analysis of CG-SBM trajectories uncovers variant-specific allosteric communication pathways linking the 630 loop to the RBD. In Omicron BA.1, distance-based correlation and sequence-space analyses identify coordinated mutations that rewire these pathways and tune RBD stability, highlighting how coordinated mutational landscapes reshape functional allostery. This thesis next investigates another multi-domain, therapeutically critical protein: the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp, nsp12), which drives viral genome replication. A simplified Cα-based CG model is used to investigate cooperative subdomain folding of RdRp, where a few critical interfacial tethering interactions are identified, supporting a fly-casting-like induced-folding mechanism involving the flexible thumb subdomain. The interplay between polymer stiffness, characterized by persistence length, and the capture radius for this induced folding is quantified, linking polymer mechanics to binding energetics. Moving beyond protein, this thesis also explores RNA folding using an electrostatics-integrated all-atom structure-based model framework that accounts for both collective and individual ion-specific stabilization arising from counterions. Application to the SAM-II riboswitch RNA aptamer reveals a multidimensional folding landscape with a Mg²⁺-mediated rate-limiting folding transition. Overall, this work demonstrates the efficiency of several multiscale structure-based modeling approaches in capturing long-timescale folding, allostery, and mutation-driven functional regulation, and ion-driven structural organization in complex biomolecular systems.

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