Development and application of QM/MM methods based on the SCC-DFTB approach

Qiang Cui, cui@chem.wisc.edu, Chemistry, University of Wisconsin, Madison, 1101
University Ave, Madison, WI 53706

Motivated by the long-term goal of understanding vectorial biological processes
such as proton transport (PT) in biomolecular ion pumps, a number of
developments were made to establish combined quantum mechanical/molecular
mechanical (QM/MM) methods suitable for studying chemical reactions involving
significant charge separation in the condensed phase. These developments will be
discussed with representative problems. Specifically, free energy perturbation
and boundary potential methods for treating long-range electrostatics were
implemented to test the robustness of QM/MM results for protein systems. It was
shown that consistent models with sufficient sampling were able to produce
quantitatively satisfactory results, such as pKa for titritable groups in the
interior of proteins, while an inconsistent treatment of electrostatics or lack
of sufficient sampling may produce incorrect results. Modifications were made to
an approximate density functional theory (SCC-DFTB) to improve the description
of proton affinity and hydrogen-bonding, which are crucial for the treatment of
PT in polar systems. Test calculations on water autoionization and diffusion
constants of proton and hydroxide in bulk water showed that both improvements
are necessary for quantitatively reliable results. Finally, the newly
established SCC-DFTB/MM-GSBP protocol was used to explore mechanistic issues in
carbonic anhydrase (CA), which revealed surprising features that have not been
discussed in previous simulation studies.