Multiscale Computational Modeling of Protein Aggregation Kinetics

SUMMARY

# Multiscale Computational Modeling of Protein Aggregation Kinetics ## Background and Rationale Protein aggregation is a hallmark of neurodegenerative diseases including Parkinson's disease, where alpha-synuclein forms pathological Lewy bodies. Understanding the molecular mechanisms governing aggregation kinetics is crucial for therapeutic development. This computational validation study employs multiscale molecular dynamics (MD) simulations to model protein aggregation processes across temporal

METHODOLOGY NOTES

Phase 1: System Preparation (Days 1-7) - Generate initial protein structures from PDB database for alpha-synuclein NAC region (residues 61-95), tau PHF6 domain, and TDP-43 C-terminal fragment. Perform energy minimization and 100ns equilibration simulations in explicit water using AMBER force field. Phase 2: Enhanced Sampling (Days 8-45) - Execute metadynamics simulations with collective variables including radius of gyration, inter-protein contacts, and secondary structure content. Run 12 replica exchange simulations per protein system spanning 300-400K temperature range. Perform 500ns production runs per replica with coordinate saving every 10ps. Phase 3: Free Energy Calculations (Days 46-75) - Calculate dimerization free energies using umbrella sampling with protein-protein distance as reaction coordinate. Sample 40 windows with 50ns simulation per window. Compute oligomerization thermodynamics for trimers and tetramers using potential of mean force calculations. Phase 4: Kinetic Ana