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Issue 36, 2012
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Convergence of QM/MM free-energy perturbations based on molecular-mechanics or semiempirical simulations

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Abstract

Lately, there has been great interest in performing free-energy perturbation (FEP) at the combined quantum mechanics and molecular mechanics (QM/MM) level, e.g. for enzyme reactions. Such calculations require extensive sampling of phase space, which typically is prohibitive with density-functional theory or ab initio methods. Therefore, such calculations have mostly been performed with semiempirical QM (SQM) methods, or by using a thermodynamic cycle involving sampling at the MM level and perturbations between the MM and QM/MM levels of theory. However, the latter perturbations typically have convergence problems, unless the QM system is kept fixed during the simulations, because the MM and QM/MM descriptions of the internal degrees of freedom inside the QM system are too dissimilar. We have studied whether the convergence of the MM → QM/MM perturbation can be improved by using a thoroughly parameterised force field or by using SQM/MM methods. As a test case we use the first half-reaction of haloalkane dehalogenase and the QM calculations are performed with the PBE, B3LYP, and TPSSH density-functional methods. We show that the convergence can be improved with a tailored force field, but only locally around the parameterised state. Simulations based on SQM/MM methods using the MNDO, AM1, PM3, RM1, PDDG-MNDO, and PDDG-PM3 Hamiltonians have slightly better convergence properties, but very long simulations are still needed (∼10 ns) and convergence is obtained only if electrostatic interactions between the QM system and the surroundings are ignored. This casts some doubts on the common practice to base QM/MM FEPs on semiempirical simulations without any reweighting of the trajectories.

Graphical abstract: Convergence of QM/MM free-energy perturbations based on molecular-mechanics or semiempirical simulations

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Article information


Submitted
29 Mar 2012
Accepted
15 Jun 2012
First published
18 Jun 2012

Phys. Chem. Chem. Phys., 2012,14, 12592-12604
Article type
Paper

Convergence of QM/MM free-energy perturbations based on molecular-mechanics or semiempirical simulations

J. Heimdal and U. Ryde, Phys. Chem. Chem. Phys., 2012, 14, 12592
DOI: 10.1039/C2CP41005B

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