| This thesis presents the study of a new approach, called EPIC (Electronic polarization from the Internal Continuum), to include electronic polarization in molecular mechanical force fields. An intramolecular dielectric continuum is shown to accurately model the electronic induction. EPIC is based on Poisson's equation, from classical electrostatics, and makes use of a dielectric function that varies in space, defining a polarizable molecular volume. The obtained partial differential equation is solved with a finite difference algorithm. The molecular dielectric function, central to EPIC, is built with atomic radii and an internal dielectric constant: empirical and adjustable parameters.The assessment of the electrostatic potential induced by a local electric perturbation shows excellent agreement between EPIC and quantum mechanics. Furthermore, a new general approach for the calculation of atomic partial charges placed in a dielectric volume is derived. These progress are tested with the calculation of the potential energy dissociation curve for a cation-pi system and a H-bonded 4-pyridone dimer, both shown to be strongly dependent on polarizability.The EPIC model is fitted uniquely on isolated molecules. Hence, the transferability of the obtained parameters to the condensed phase is verified by comparing experimental refractive indices with the optical dielectric constants that are calculated by applying EPIC at a molecular level on liquid droplets obtained from molecular dynamic simulations. The correlation shows a unitary slope and a coefficient 0.95.Free energy of hydration calculations on 485 solutes show that the permanent electrostatic potential, the electronic induction and the electrical response from an implicit solvent model are simultaneously obtained with the same set of parameters. This demonstrates the physical soundness of the EPIC model. The research on implicit solvent models forces us to challenge certain dogmas on the signification of traditionaly used parameters and to propose a 3-zone dilectric function that better reflects the underlying physical principles. The decoupling of each of the fitting steps is a considerable advantage for the generalisation of the EPIC model.The chosen empirical parameters are optimized with a new numerical procedure for the calculation of the polarizability tensor resulting from a dielectric volume. The agreement between the EPIC molecular polarizabilities and those obtained with quantum mechanics or experiment exceeds literature precedents, especially because of the much smaller number of fitted parameters required. The polarizability anisotropy is accurately modeled without the extra complexity necessary in previous polarizable models. EPIC is validated on a dataset containing 707 polarizability tensors calculated with B3LYP for this study. Thereby, the presented optimized parameters can account for the polarizability of a wide variety of functional chemical groups found in biomolecules and bioorganic chemistry.A general polarizable force field has the potential to greatly improve the predictive power of molecular simulations. The accurate electrostatic EPIC model needs few adjustable parameters and, hence, could form the cornerstone for the development of a general and more accurate polarizable force field, which could have important impacts in many areas such as drug design, biological processes understanding, etc.Keywords: Force field, molecular mechanics, polarisability, electronic polarisation, electrostatic potential, dielectric, Poisson-Boltzmann, parameterization, DRESP, EPIC. |
