Comparison of linear-scaling semiempirical methods and combined quantum mechanical/molecular mechanical methods applied to enzyme reactions

Stephen J. Titmuss, Peter L. Cummins, Andrey A. Bliznyuk, Alistair P. Rendell, Jill E. Gready

Research output: Contribution to journalArticlepeer-review

35 Citations (Scopus)

Abstract

Two theoretical methodologies - a combined quantum mechanical and molecular mechanical (QM/MM) model and a linear-scaling semiempirical SCF method (MOZYME) - were used to calculate energy profiles for an enzyme reaction path, that for hydride-ion transfer between 8-methylpterin and nicotinamide adenine dinucleotide phosphate (NADPH) in dihydrofolate reductase (DHFR). Profiles from the QM/MM model, which divides the system into QM and MM regions, were compared with those from MOZYME, which treats the entire ligand-protein complex quantum mechanically. If the coordinates of the MM region vary little, it is possible to define a QM/MM model for the DHFR reaction that gives energetics close to those from MOZYME. However, the QM/MM and MOZYME energies diverge when the MM geometry changes, largely due to the MM electrostatic energy. 'Switching off' polarisation of the QM region by the MM region produced larger changes especially in the transition-state region. The results suggest caution should be used when generating reaction paths for QM/MM methods.

Original languageEnglish
Pages (from-to)169-176
Number of pages8
JournalChemical Physics Letters
Volume320
Issue number1-2
DOIs
Publication statusPublished - 31 Mar 2000
Externally publishedYes

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