Frozen orbital QM/MM methods for density functional theory

We have developed a density functional (DFT) version of our quantum chemistry/molecular mechanics (QM/MM) methodology based on using frozen molecular orbitals as the interface between the QM and MM regions. The methodology is distinguished from previous frozen orbital work by the availability of an accurate analytical gradient for ab initio methods and by the construction of a QM/MM interface capable of reproducing both deprotonation energies and conformational energetics around the frozen bond via fitting of interface parameters to a small model molecule. Results are presented for several test cases, including the alanine tetrapeptide and four amino acid side chains. Excellent agreement between fully QM DFT calculations and the QM/MM calculations is obtained for both conformational energetics and deprotonation energies in all cases.