enhanced-sampling

Enhanced Sampling

Description

This skill covers enhanced sampling methods for atomistic MD simulations where rare events, large free-energy barriers, or slow conformational transitions prevent standard MD from converging on accessible timescales. It addresses collective variable (CV) selection and validation; umbrella sampling with WHAM/MBAR reconstruction; well-tempered metadynamics; adaptive biasing force; steered MD; temperature replica exchange; accelerated MD; free-energy surface convergence diagnostics; and PLUMED integration with GROMACS, LAMMPS, and ML interatomic potentials. Invoke this skill whenever a process of interest has an estimated barrier ≳ 10 k_B T or an estimated timescale that cannot be sampled directly within the available simulation budget.

Domain Context

Standard MD is limited to continuous trajectories. For a system at 300 K, barrier-crossing events with ΔG‡ ≳ 10 k_B T (≳ 25 kJ/mol) occur with rates of order k ~ ν exp(−ΔG‡/k_B T) ≈ 10¹³ × e⁻¹⁰ s⁻¹ ≈ 10⁻⁸ s⁻¹ — a mean first-passage time of ~100 ns. Protein folding, crystal nucleation, ion permeation through channels, and solid-state diffusion all fall into this regime.

Enhanced sampling methods modify the system to accelerate barrier crossing and then reconstruct the unbiased free energy surface (FES) from the biased simulation. The modifications take four forms:

1. Bias potentials on collective variables (CVs): A time-varying or history-dependent potential V_bias(ξ) is added along one or more CVs ξ(r). The CV must capture the reaction coordinate — it must separate the metastable states and project out the slow degrees of freedom. A poor CV does not accelerate the relevant transition even if the method runs correctly.
2. Hamiltonian or temperature ladders (replica exchange): Multiple copies of the system run in parallel at different temperatures or with different Hamiltonians. Exchanges between replicas are accepted with the Metropolis criterion, enabling high-temperature configurations to escape local minima and donate configurations to lower-temperature replicas.
3. Time-independent bias (flat histogram): The WAN to-WHAM or MBAR approach reconstructs the FES from multiple biased simulations (umbrella sampling windows) by reweighting each frame by the inverse of its bias weight.
4. Velocity-boosted or modified-potential approaches (accelerated MD): A dihedral or total boost potential is added to reduce barriers globally rather than along a specific CV.