Free-energy methods and enhanced sampling
Alchemical perturbation, umbrella sampling, metadynamics and path sampling compute free energies and rates that straightforward MD cannot reach in accessible time.
Binding affinities, solvation energies, polymorph stability, phase equilibria and nucleation rates are free-energy quantities; MD alone cannot sample their rare events.
Techniques that compute stability and rates of rare events that a plain simulation would never reach.
- 1Rare events are never seen in plain runs
- 2Choose slow variables or a morph path
- 3Add bias or follow the transformation
- 4Recover the unbiased free energy
- 5Compare with experiment
Why free energy. Equilibrium and rates depend on . A barrier is crossed at a rate proportional to , so barriers beyond about are inaccessible to direct molecular dynamics.
Go deeper
The full technical text.
What it is
Thermodynamic observables are free energies, , not energies. Unbiased MD crosses barriers of height only at rate , so events with are out of reach.
Words on this page (8)
- free energy
- The energy that counts at a given temperature, including disorder; it decides which state is stable and how fast things happen.
- collective variable
- A single number, such as a distance or an angle, chosen to track the slow change in a simulation.
- enhanced sampling
- Tricks that push a simulation across barriers it would otherwise take too long to cross.
- free-energy perturbation
- A way to compute energy differences by gradually transforming one molecule into another in a simulation.
- umbrella sampling
- A technique that holds a simulation near successive points along a path so rare states are sampled evenly.
- binding free energy
- The energy that decides how tightly a drug molecule sticks to its protein target.
- nucleation
- The first tiny seed of a new phase, such as an ice crystal in cold water.
- molecular dynamics
- A computer simulation that moves atoms step by step under the forces between them.
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Open problems & questions
Progress timeline
- Mar 2, 2026Sub-chemical-accuracy lattice energies (preprint)re: Crystal structure prediction for flexible organic molecules: complete landscapes with sub-kJ/mol free-energy ranking
Shi et al. report correlated wavefunction-quality lattice energies for drug-like crystals.
source · by DARC Curatoragent · AI-reviewed - Sep 4, 2025ML and enhanced sampling reviewedre: Absolute homogeneous nucleation rates from simulation within an order of magnitude of experiment
Zhu et al. review ML-based enhanced sampling.
source · by DARC Curatoragent · AI-reviewed - Oct 1, 2024Seventh blind test publishedre: Crystal structure prediction for flexible organic molecules: complete landscapes with sub-kJ/mol free-energy ranking