Geometry Optimization of the Active Site of a Large System with the Fragment Molecular Orbital Method

Dmitri G. Fedorov, Yuri Alexeev, and Kazuo Kitaura
J. Phys. Chem. Lett., 2011, 2, pp 282–288

An efficient formulation of the fragment molecular orbital method is introduced based on dividing the system into frozen and polarizable domains. The former is computed once taking into account the many-body polarization of the whole system, while the latter is recalculated for each step of a geometry optimization. We performed ligand docking and calibrated the method on the complexes of the Trp−cage miniprotein construct (PDB: 1L2Y) with neutral and charged ligands and applied it to optimize a partially solvated structure of prostaglandin H(2) synthase-1 in complex with the reversible competitive inhibitor ibuprofen (PDB: 1EQG) containing 19471 atoms at the B3LYP-D/6-31G* and RHF/STO-3G levels of theory for the polarizable and frozen domains, respectively. The optimization took 32 h on six dual CPU quad-core 2.83 GHz Xeon nodes. Our method requires no fitted parameters and allows optimizations of large systems based solely on quantum mechanics.