Quantifying the Catalytic Effect of the EGFR Kinase Environment on Osimertinib Covalent Binding

This dataset contains all computational data for the paper "Quantifying the Catalytic Effect of the EGFR Kinase Environment on Osimertinib Covalent Binding". Research Focus: We demonstrate how the EGFR kinase domain actively catalyzes osimertinib's Michael addition to CYS797, achieving rate accelerations >10³²-fold over solution-phase reactions through geometric pre-organization and transition state stabilization. Dataset Contents: 1. Molecular Dynamics Simulations (17.36 GB total) - MD.dcd (16.79 GB): Production MD trajectory capturing EGFR-osimertinib conformational sampling - Equilibration.dcd (335 MB): System equilibration phase - Annealing.dcd (96 MB): Temperature annealing for conformational diversity - Minimization.dcd (13.4 MB): Energy minimization trajectory - MD.rar (11 MB): All input files, CHARMM36 parameters, topology, and analysis scripts for catalytic geometry sampling 2. Quantum Mechanical Calculations (438 MB total) - quantum_chemistry_calc.rar (438 MB): ORCA calculations quantifying catalytic effects: - Transition state optimizations for Michael addition (10.4-13.7 kcal/mol barriers) - Frequency calculations confirming transition states - Energy computations showing 40-44 kcal/mol reduction vs. aqueous reaction - Reactant and product state calculations - Input files for barrier distribution analysis (10.4-148.5 kcal/mol range) Computational Methodology: - MD: NAMD/CHARMM with CHARMM36 force field, explicit solvent - QM: ORCA 6.0, B3LYP-D3/def2-TZVP level for accurate barrier calculations - Integration: Snapshots from MD used as starting points for QM transition state searches Key Findings Supported by This Data: 1. EGFR reduces Michael addition barrier from ~54 kcal/mol (in water) to 10.4-13.7 kcal/mol 2. Rate accelerations exceed 10³²-fold through enzymatic catalysis 3. Wide barrier distribution (10.4-148.5 kcal/mol) reveals importance of geometric pre-organization 4. Synergistic effects of proximity, orientation, and transition state stabilization Usage: - MD trajectories: Analyze catalytic conformations in VMD/MDAnalysis - QM calculations: Reproduce barrier computations in ORCA - Integration: Study structure-reactivity relationships for covalent inhibition Related Publication: Darous Kent Joboe and Peter R. Taylor, "Quantifying the Catalytic Effect of the EGFR Kinase Environment on Osimertinib Covalent Binding", Journal of Chemical Information and Modeling (submitted)