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

Two theoretical methodologies - a combined quantum mechanical and molecular mechanical (QM/MM) model and a Linear-scaling semiempirical SCF method (MO ZYME) - were used to calculate energy profiles for an enzyme reaction path, that for hydride-ion transfer between 8-methylpterin and nicotinamide aden ine dinucleotide phosphate (NADPH) in dihydrofolate reductase (DHFR). Profi les 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-protei n complex quantum mechanically. If the coordinates of the MM region vary li ttle, it is possible to define a QM/MM model for the DHFR reaction that giv es energetics close to those from MOZYME. However, the QM/MM and MOZYME ene rgies diverge when the MM geometry changes, largely due to the MM electrost atic energy. 'Switching off' polarisation of the QM region by the MM region produced larger changes especially in the transition-state region. The res ults suggest caution should be used when generating reaction paths for QM/M M methods. (C) 2000 Published by Elsevier Science B.V. All rights reserved.