Sunday, September 9, 2012

Dispersion corrections and bio-molecular structure and reactivity

Richard Lonsdale, Jeremy N. Harvey, and Adrian J. Mulholland "Effects of Dispersion in Density Functional Based QM/ MM Calculations on Cytochrome P450 Catalysed Reactions"Journal of Chemical Theory and Computation 2012, ASAP (Paywall)

The DFT dispersion correction developed by Grimme and co-workers was recently highlighted in Computation Chemistry Highlights. Recently two papers have appeared that quantify the importance of the dispersion correction on modeling bio-molecular structure and reactivity.

Cytochrome P450 barrier heights in better agreement with experiment using B3LYP-D2 and -D3
Lonsdale et al. used QM/MM to compute barrier heights for oxidation reactions, catalyzed by P450$_{cam}$, with an without dispersion corrections in the QM region.  Invariably the dispersion correction lowered the barrier significantly (usually by ca 5 kcal/mol), yielding results that were in better agreement with experimental values.  The effect of the dispersion correction on the transition state geometries was less pronounces though not negligible, with bond lengths changing by as much as 0.2 Å.

It is worth noting that the QM region contains a conjugated porphyrin ring and that three of the four substrates considered in the study contain one or more double bonds.  Thus, the QM region contains very polarizable functional groups and, since the magnitude of dispersion interactions increases with the polarizability of the groups involved, it is possible that the effect of dispersion on barrier heights for other enzymes will be less than observed here.  It will be interesting to find out.

MP2 quality Trp-cage structure using RHF-D
Nagata et al. have implemented analytical MP2/PCM gradients for the fragment molecular orbital method and used it to geometry optimize the small protein Trp-cage at the MP2/6-31(+)G(d) level of theory [the (+) indicates diffuse functions on carboxylate groups].  The resulting structure compared well with the experimental NMR structures, with a backbone RMSD of only 0.426 Å. This is a significant improvement in agreement compared to the corresponding RHF/PCM optimized structure (RMSD 1.107 Å) and demonstrates the importance dispersion in bio-molecular structure.  Interestingly, the corresponding RHF-D structure compared equally well to experiment (0.414 Å) and was virtually identical to the MP2 structure (RMSD 0.068 Å).

Disclaimer: I was involved in the implementation of the FMO RHF/PCM interface.