Anisotropic, Polarizable Molecular Mechanics Studies of Inter- and Intramolecular Interactions and Ligand-Macromolecule Complexes. A Bottom-Up Strategy.
We present an overview of the SIBFA polarizable molecular mechanics procedure, which is formulated and calibrated on the basis of quantum chemistry (QC). It embodies nonclassical effects such as electrostatic penetration, exchange-polarization, and charge transfer. We address the issues of anisotropy, nonadditivity, and transferability by performing parallel QC computations on multimolecular complexes. These encompass multiply H-bonded complexes and polycoordinated complexes of divalent cations. Recent applications to the docking of inhibitors to Zn-metalloproteins are presented next, namely metallo-beta-lactamase, phosphomannoisomerase, and the nucleocapsid of the HIV-1 retrovirus. Finally, toward third-generation intermolecular potentials based on density fitting, we present the development of a novel methodology, the Gaussian electrostatic model (GEM), which relies on ab initio-derived fragment electron densities to compute the components of the total interaction energy. As GEM offers the possibility of a continuous electrostatic model going from distributed multipoles to densities, it allows an inclusion of short-range quantum effects in the molecular mechanics energies. The perspectives of an integrated SIBFA/GEM/QM procedure are discussed.
Gresh
Nohad
N
Laboratoire de Pharmacochimie Moléculaire et Cellulaire, U648 INSERM, UFR Biomédicale, Université René-Descartes, 45, rue des Saints-Pères, 75006 Paris, France, Laboratory of Structural Biology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, and Laboratoire de Chimie Théorique, Université Pierre-et-Marie-Curie, UMR 7616 CNRS, case courrier 137, 4, place Jussieu, 75252 Paris, France.
Cisneros
G Andrés
GA
Darden
Thomas A
TA
Piquemal
Jean-Philip
JP