A primer on molecular dynamics

Abstraction: End-to-end introduction to MD simulation workflow, force fields, and free energy methods

Key points:

• MD workflow: (1) define system - protein in water box with ions + periodic boundary conditions; (2) choose force field (AMBER, CHARMM, GROMOS); (3) energy minimization via gradient descent on positions; (4) equilibration with thermostat/barostat; (5) production simulation at femtosecond timesteps
• Force field potential energy = bond stretches + bond angles + dihedral torsions + Lennard-Jones van der Waals (r^-12 repulsion, r^-6 attraction) + electrostatics; forces are negative gradient of this potential
• Femtosecond timestep limit (numerical instability) means protein folding (microseconds-milliseconds) is generally inaccessible by brute force; enhanced sampling methods (metadynamics, replica exchange MD, accelerated MD) overcome this
• Alchemical free energy perturbation uses coupling parameter λ (0→1) to estimate ΔG between two states (e.g., ligand bound vs. unbound) via the Zwanzig relationship; avoids enumerating all conformations
• Case study: Relay Therapeutics used 25 µs MD simulations (Amber99SB*-ILDN force field) to identify FGFR2 P-loop as a selectivity handle, leading to FGFR2-selective inhibitor lirafugratinib (RLY-4008)
• QM/MM hybrid methods apply quantum mechanics to a small active region and classical force fields to the rest; polarizable force fields (e.g., AMOEBA) partially capture electron charge distribution classically

Connections: Molecular Dynamics · Protein Folding · Computational Chemistry · Free Energy Calculations

Source: https://www.owlposting.com/p/a-primer-on-molecular-dynamics