Quantum Regions, Sampled Properly
Quantum regions embedded in molecular mechanics, and enhanced sampling with WHAM, TI, FEP, BAR and MBAR analysis.
1 Checked (exact)8 PartialEngine 1.10.12 live
What You Can Compute
QM/MM
HF, DFT or MP2 regions (up to 60 QM atoms, 600 atoms in all) inside MMFF94 with additive or subtractive schemes and analytic gradients: energy, optimisation and dynamics.
Potentials of Mean Force
Umbrella sampling with WHAM along distances, angles and dihedrals. Sampling and free energy methods run on MMFF94, Lennard-Jones and model systems up to 200 MM atoms.
Alchemical Free Energy
TI, FEP, BAR and MBAR with blocking and bootstrap error bars; ABF, REST2, GaMD and OPES.
End-Point and Cycle Tools
MM/GBSA and MM/PBSA binding energies, free energy cycle closure with hysteresis per loop, and constant-pH titration of point-charge sites.
Every Method, with Its Level of Support
Generated from the engine's own capability report (engine 1.10.12), so this list never runs ahead of the code.
Checked reproduces printed values Checked (exact) no printed value exists; checked against exact mathematics or brute force Partial code exists, unchecked parts badged in the app Unverified built, no printed check yet
| Method | Support | Since | Primary Sources |
|---|---|---|---|
| QM/MM (additive and subtractive)HF, DFT or MP2 regions in MMFF94 with electrostatic embedding and link atoms. No paper prints a value for QM/MM with this force field. Checked against exact properties: the gradient of the embedded QM energy, on the QM atoms and on the MM charges, equals finite differences of the energy within 1e-7 Eh/bohr for Hartree-Fock (closed and open shell) and MP2 regions and within 1e-6 for a PBE region; the complete QM/MM gradient with a link atom and the MMFF94 terms equals finite differences within 3e-7 kcal/mol/A for a Hartree-Fock region in six combinations of additive or subtractive scheme, electrostatic or mechanical embedding and three boundary-charge schemes, and has no net force or torque; a QM region equal to the whole system returns the plain QM energy and gradient; a distant chloride ion in the MM region reproduces the all-QM interaction energy with water within 1e-6 kcal/mol in a minimal basis. Not checked: hybrid functionals and large basis sets inside the QM region, DFT and MP2 regions together with link atoms, and regions near the 60 atom limit. Up to 60 QM atoms. | Checked (exact) | 0.7.45 | Warshel, Levitt 1976; Senn, Thiel 2009 |
| Umbrella sampling with WHAMPotentials of mean force along distances, angles and dihedrals. Runs on MMFF94, Lennard-Jones and model systems (up to 200 MM atoms). QM/MM umbrella sampling is not offered. | Partial | 0.7.45 | Torrie, Valleau 1977; Kumar et al. 1992 |
| Alchemical free energy (TI, FEP, BAR, MBAR)Free energy differences with blocking and bootstrap errors. | Partial | 0.7.45 | Zwanzig 1954; Bennett 1976; Shirts, Chodera 2008 |
| Metadynamics and replica exchangeStandard and well-tempered metadynamics, temperature replica exchange. | Partial | 0.7.45 | Laio, Parrinello 2002; Sugita, Okamoto 1999 |
| QM/MM response propertiesPolarizability, TDHF, TDA and TDDFT excitations and Raman of a QM region embedded in fixed MM point charges. Tested only with the embedding charge set to zero, by three identities: the polarizability equals that of the plain polarizability tool within 2e-5 a.u. (water, Hartree-Fock, 6-31G*), and the Raman frequencies and activities equal those of the plain Raman tool within 0.5 cm-1 and 0.5 percent (water, Hartree-Fock, STO-3G). Nothing is tested with non-zero charges, and the excitation energies have no test. Fixed charges, no MM polarisation, no boundary treatment inside the tool, HF and Kohn-Sham only, at most 10 QM atoms for Raman. | Partial | 1.8.0 | Senn, Thiel 2009; Porezag, Pederson 1996 |
| ABF, REST2, GaMD, OPES and multiple walkersAdaptive biasing force, replica exchange with solute tempering, Gaussian accelerated MD and OPES. REST2 on model systems only. | Partial | 1.5.0 | Wang, Friesner, Berne 2011; Miao, Feher, McCammon 2015; Invernizzi, Parrinello 2020 |
| End-point binding energy (MM/GBSA and MM/PBSA)Binding free energy of a complex from MM/GBSA and MM/PBSA end-point calculations on snapshots, with per-term decomposition. The entropy term is not computed. HCT scale factors must be supplied; GBn2 and Poisson-Boltzmann forces are refused. No distributed program value reproduced. | Partial | 1.4.0 | Kollman et al. 2000; Onufriev, Bashford, Case 2004 |
| Free energy cycle closureCycle closure of a relative free energy map: node free energies, corrected edges and hysteresis per loop from FEP, TI or BAR edge values with their uncertainties. Works on edge values you supply or computed elsewhere in the Lab; it does not compute the edges. | Partial | 1.9.0 | Wang et al. 2013 |
| Constant-pH titrationDiscrete-protonation Monte Carlo titration of point-charge sites with reference pKa values, giving an apparent pKa per site. The six built-in reference pKa values are those of Mongan, Case, McCammon 2004 Table 1; an isolated site titrates on the Henderson-Hasselbalch curve at its reference pKa, which is an identity of the method. Interacting sites are checked for the sign of the shift only. No printed titration result is reproduced: the lysozyme values of that paper need constant-pH molecular dynamics in generalised Born solvent, which is not built. Not coupled to molecular dynamics. | Partial | 1.9.0 | Mongan, Case, McCammon 2004 |
Printed Value, Our Value
No printed-value rows are listed for this domain yet. Self-tests and cross-checks are described on the Validation page.
Exact Checks
Our output against exact mathematics or a recomputation inside the engine, never another program. These are not printed-value checks and are counted separately.
| Quantity | Checked Against | Tolerance | Ours | Result |
|---|---|---|---|---|
| QM/MM Gradient with a Link Atom and MMFF94 Terms, Hartree-Fock Region, Six Scheme Combinations, 30 Coordinates Each | 4-point finite differences of the QM/MM energy | 3e-7 kcal/mol/A | largest 1.2e-7 | Within tolerance |
| Gradient of the Embedded QM Energy on QM Atoms and MM Charges: RHF, UHF and MP2 in STO-3G, RHF in def2-SVP, PBE in STO-3G | 4-point finite differences of the embedded energy | 1e-7 Eh/bohr (PBE 1e-6) | largest 6.1e-10 | Within tolerance |
| Water in the QM Region with a Chloride Ion in the MM Region at 8, 12 and 20 A, Minimal Basis: Interaction Energy | All-QM interaction energy of the same pair | 1e-6 kcal/mol | largest 3.7e-10 | Within tolerance |
Not Offered Today
- Umbrella sampling, FEP and TI driven by QM/MM forces
- QM regions larger than 60 atoms
- Biomolecular force fields inside QM/MM (MMFF94 only)
- Entropy in MM/GBSA
- Constant-pH coupled to molecular dynamics
In the Chemistry Lab
Start, then Large systems and dynamics, then the Sampling option. Pick the collective variable and windows; the Queue shows each window as its own row.
QM/MM and Free Energy Questions
Which QM methods can I embed?
How are free energy errors given?
Is MM/GBSA available?
See It on a Molecule of Your Own
See your own molecule optimised, its spectrum computed and the printed reference values shown beside the result.