Hybrid QM/MM methods

### Presentations

04/12/2013, Cambridge, Electronic Structure Discussion Group at Cavendish Laboratory

16/01/2014, New York, Stony Brook University, AMBER Developers Meeting

### Articles

The adaptive buffered force QM/MM method in the CP2K and AMBER software packages__L Mones__, A Jones, AW Götz, T Laino, RC Walker, B Leimkuhler, G Csanyi and N Bernstein

2015,

*Journal of computational chemistry 36 (9), 633-648*

**Abstract**: The implementation and validation of the adaptive buffered force (AdBF) quantum-mechanics/molecular-mechanics (QM/MM) method in two popular packages, CP2K and AMBER are presented. The implementations build on the existing QM/MM functionality in each code, extending it to allow for redefinition of the QM and MM regions during the simulation and reducing QM-MM interface errors by discarding forces near the boundary according to the buffered force-mixing approach. New adaptive thermostats, needed by force-mixing methods, are also implemented. Different variants of the method are benchmarked by simulating the structure of bulk water, water autoprotolysis in the presence of zinc and dimethyl-phosphate hydrolysis using various semiempirical Hamiltonians and density functional theory as the QM model. It is shown that with suitable parameters, based on force convergence tests, the AdBF QM/MM scheme can provide an accurate approximation of the structure in the dynamical QM region matching the corresponding fully QM simulations, as well as reproducing the correct energetics in all cases. Adaptive unbuffered force-mixing and adaptive conventional QM/MM methods also provide reasonable results for some systems, but are more likely to suffer from instabilities and inaccuracies.

Tests of an Adaptive QM/MM Calculation on Free Energy Profiles of Chemical Reactions in Solution

C Varnai, N Bernstein,

__L Mones__and G Csanyi

2014,

*The Journal of Physical Chemistry B 117 (40), 12202-12211*

**Abstract**: We present reaction free energy calculations using the adaptive buffered force mixing quantum mechanics/molecular mechanics (bf-QM/MM) method.1 The bf-QM/MM method combines nonadaptive electrostatic embedding QM/MM calculations with extended and reduced QM regions to calculate accurate forces on all atoms, which can be used in free energy calculation methods that require only the forces and not the energy. We calculate the free energy profiles of two reactions in aqueous solution: the nucleophilic substitution reaction of methyl chloride with a chloride anion and the deprotonation reaction of the tyrosine side chain. We validate the bf-QM/MM method against a full QM simulation, and show that it correctly reproduces both geometrical properties and free energy profiles of the QM model, while the electrostatic embedding QM/MM method using a static QM region comprising only the solute is unable to do so. The bf-QM/MM method is not explicitly dependent on the details of the QM and MM methods, so long as it is possible to compute QM forces in a small region and MM forces in the rest of the system, as in a conventional QM/MM calculation. It is simple, with only a few parameters needed to control the QM calculation sizes, and allows (but does not require) a varying and adapting QM region which is necessary for simulating solutions.

### Book chapters

Adaptive and Accurate Force-Based QM/MM CalculationsN Bernstein, I Solt,

__L Mones__, C Varnai, SA Winfield and G Csanyi

2014,

*Computational Approaches to Protein Dynamics*

**Abstract**: To begin addressing this problem, we have developed the bu ered-force QM/MM (bf-QM/MM) method based on a similar approach used for solid state systems [6,7]. e bf-QM/MM method allows for adaptivity of the set of QM atoms, letting functional groups and molecules move into and out of the QM region. e challenge in adaptive simulations is to prevent the inevitable errors at the interface between the two methods from building up over time by systematically transporting atoms into or out of the QM region. By reducing the errors in the forces on atoms near the interface, we reduce the size of artifacts in observables computed from the molecular dynamics trajectories. e resulting method produces stable, long-running simulations with adaptively changing QM regions. We note that we do not present dynamic simulation results for proteins here, only an initial evaluation of the performance and accuracy of the bf-QM/MM method when applied to small solutes in water. For proteins we only present calculations of force errors at the center of the QM region for congurations taken from an equilibrium MM trajectory as a function of QM region size, to show the e ect of the QM-MM interface in this type of system and to guide the selection of appropriate QM regions in future work.