• Development of the Drude Polarizable Force Field for Molecular Dynamics Simulation

      Lin, Fang-Yu; MacKerell, Alexander D., Jr.; 0000-0003-0103-0167 (2019)
      Molecular dynamics (MD) simulations have been widely applied to study biomolecular systems. While MD simulations have been used in a variety of applications, the accuracy of the results depends strongly on the force field (FF) used. The commonly used FFs are additive or non-polarizable FFs. However, one limitation of the additive FFs is the lack of electronic polarizability to treat molecules. To overcome this, an attractive approach is to introduce the explicit treatment of electronic polarizability into the potential energy function known as polarizable FFs. In Chapter 1, an overview of the CHARMM empirical FF as well as the development and application of the polarizable CHARMM FF based on the classical Drude oscillator is presented. As noncovalent halogen bonding interactions between halogenated ligands and proteins are important in drug design, a well-parametrized polarizable FF for halogen containing compounds is required to perform more accurate modeling of halogenated molecules. During the course of this development, a significant contribution of halogen-hydrogen bond donor (X-HBD) interactions to ligand-protein complexes was uncovered in addition to halogen bond (XB) interactions (Chapter 2). In Chapter 3, the development of halogen polarizable FF to both aliphatic and aromatic systems using halogenated ethane and benzene model compounds is illustrated, with emphasis on optimizing both X-HBD and XB interactions as discussed in Chapter 2. To assure good reproduction of X-HBD interactions with proteins, further optimization of atom pair-specific Lennard-Jones (LJ) parameters is required for both the polarizable and non-polarizable halogen FFs (Chapter 4). Finally, Chapter 5 presents the current optimization of polarizable protein FF to yield a more accurate description of the polarization response in simulations. The resulting protein FF, referred to as Drude-2019, will be more applicable in the study of biomolecular systems. Overall, the advances made in this dissertation will facilitate important discoveries of a range of chemical and biological phenomena.