Browsing by Subject "QM/MM"

Now showing 1 - 6 of 6
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    Charge-dependent non-bonded interaction methods for use in quantum mechanical modeling of condensed phase reactions
    (2015-10) Kuechler, Erich
    Molecular modeling and computer simulation techniques can provide detailed insight into biochemical phenomena. This dissertation describes the development, implementation and parameterization of two methods for the accurate modeling of chemical reactions in aqueous environments, with a concerted scientific effort towards the inclusion of charge-dependent non-bonded non-electrostatic interactions into currently used computational frameworks. The first of these models, QXD, modifies interactions in a hybrid quantum mechanical/molecular (QM/MM) mechanical framework to overcome the current limitations of ‘atom typing’ QM atoms; an inaccurate and non-intuitive practice for chemically active species as these static atom types are dictated by the local bonding and electrostatic environment of the atoms they represent, which will change over the course of the simulation. The efficacy QXD model is demonstrated using a specific reaction parameterization (SRP) of the Austin Model 1 (AM1) Hamiltonian by simultaneously capturing the reaction barrier for chloride ion attack on methylchloride in solution and the solvation free energies of a series of compounds including the reagents of the reaction. The second, VRSCOSMO, is an implicit solvation model for use with the DFTB3/3OB Hamiltonian for biochemical reactions; allowing for accurate modeling of ionic compound solvation properties while overcoming the discontinuous nature of conventional PCM models when chemical reaction coordinates. The VRSCOSMO model is shown to accurately model the solvation properties of over 200 chemical compounds while also providing smooth, continuous reaction surfaces for a series of biologically motivated phosphoryl transesterification reactions. Both of these methods incorporate charge-dependent behavior into the non-bonded interactions variationally, allowing the ‘size’ of atoms to change in meaningful ways with respect to changes in local charge state, as to provide an accurate, predictive and transferable models for the interactions between the quantum mechanical system and their solvated surroundings.
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    Development of fragment-based quantum mechanical methods and combined quantum mechanical and molecular mechanical methods
    (2014-08) Wang, Yingjie
    This thesis is dedicated to develop fragment-based QM methods and QM/MM schemes: For the first part, the fragment-based explicit polarization (X-Pol) method has been extended in three aspects: I. the inclusion of exchange repulsion terms in the X-Pol model is examined by antisymmetrizing the X-Pol Hartree-product wave function; this yields X-Pol with full eXchange, called X-Pol-X; II. the original X-Pol method, where all fragments are treated using the same electronic structure theory, is extended to a multilevel representations, called multilevel X-Pol, in which different electronic structure methods are used to describe different fragments; III. a fragment-based variational many-body (VMB) expansion method is described to directly account for exchange repulsion, charge delocalization (charge transfer) and dispersion interactions in the X-Pol method. For the second part, a universal QM/MM scheme, the projected hybrid orbital (PHO) method, is proposed to handle the covalent boundary at QM/MM interface at ab initio level with arbitrary basis sets. As an extension to the generalized hybrid orbital (GHO) method in which hybrid orbitals are constructed using the valence orbitals on the boundary atom, the PHO method further represents the core and valence electrons with a secondary, minimal basis set by projecting the original (primary) basis set used in the QM system. The PHO method is then validated on several aspects: geometry optimization, charge population and proton-affinity calculation. Comparison with standard QM results shows that PHO is a robust and balanced QM/MM scheme that yields satisfactory structural, electronic, and energetic properties.
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    Development of novel schemes for treating subsystem boundaries and electrostatic potentials in simulations of complex systems
    (2014-01) Wang, Bo
    Fragmentation schemes provide a powerful strategy for calculating the potential energy surfaces of complex systems. The combined quantum mechanical and molecular mechanical (QM/MM) method, the electrostatically embedded many-body (EE-MB) method, and the molecular tailoring approach (MTA) are three examples. Two critical issues to be addressed in these methods are the treatment of the boundary between the subsystems when it passes between bonded atoms and the inclusion of the electrostatic potential of one subsystem in the Hamiltonian of another. This thesis involves the development and application of new schemes to treat both issues. The first part focuses on the development of a tuned pseudoatom scheme with a balanced redistributed charge algorithm to accurately model the QM-MM boundary that passes through a covalent bond, especially a polar covalent bond. Various redistribution schemes and ways of tuning the boundary treatments are tested and compared for the QM/MM method and the EE-MTA method. The second part of this thesis involves the development of screened charge models to include charge penetration and screening effects in generating electrostatic potentials for use in various methods, including QM/MM and EE-MB methods. The screened charge models are also used to derive partial atomic charges by fitting electrostatic potentials.
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    Development of polarizable force fields for proteins
    (2008-12) Xie, Wangshen
    This work describes the development of the polarizable force field for proteins based on classical mechanics, electronic structure theory and the combined quantum mechanical molecular mechanical method. In the first model, the classical force field is augmented with the explicit polarization energy term yielding a polarizable intermolecular potential function (PIPF). The polarizable atom sites in the system respond to the electric field by generating induced dipole moment at each site. The PIPF potential is optimized for amides and alkanes which are building blocks of proteins. The molecular dynamics simulations using the PIPF potential yield comparable or better energetics and geometries of the model compounds. In order to speed up the convergence of the induced dipole moments in the PIPF potential when all intramolecular interactions are included, we proposed a coupled polarization matrix inversion and iteration method (CPII). We were able to achieve convergence within 15 iterations for all the systems under consideration in which the iterative method shows divergence or oscillation. The second model, called the explicit polarization model (X-Pol), accounts for the polarization and charge transfer effects by treating all the fragments of the system using electronic structure theory. A variational version of the X-Pol potential is derived which facilitates the calculation of analytical gradient of energy needed for molecular dynamics simulations. Furthermore, the X-Pol potential is augmented with the buffer zone by calculating the two-electron Coulomb integrals between adjacent fragments in protein. The introduction of buffer zone in the X-Pol potential improves the convergence and the transferability of semiempirical parameters in the X-Pol potential. The molecular dynamics simulation of a solvated bovine pancreatic trypsine inhibitor reveals significant polarization and charge transfer effects in the protein.
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    Insights into Proton-Coupled Electron Transfer from Computation
    (2014-06) Provorse, Makenzie
    Proton-coupled electron transfer (PCET) is utilized throughout Nature to facilitate essential biological processes, such as photosynthesis, cellular respiration, and DNA replication and repair. The general approach to studying PCET processes is based on a two-dimensional More O'Ferrall-Jencks diagram in which electron transfer (ET) and proton transfer (PT) occur in a sequential or concerted fashion. Experimentally, it is difficult to discern the contributing factors of concerted PCET mechanisms. Several theoretical approaches have arisen to qualitatively and quantitatively investigate these reactions. Here, we present a multistate density functional theory (MSDFT) method to efficiently and accurately model PCET mechanisms. The MSDFT method is validated against experimental and computational data previously reported on an isoelectronic series of small molecule self-exchange hydrogen atom transfer reactions and a model complex specifically designed to study long-range ET through a hydrogen-bonded salt-bridge interface. Further application of this method to the hydrogen atom abstraction of ascorbate by a nitroxyl radical demonstrates the sensitivity of the thermodynamic and kinetic properties to solvent effects. In particular, the origin of the unusual kinetic isotope effect is investigated. Lastly, the MSDFT is employed in a combined quantum mechanical/molecular mechanical (QM/MM) approach to explicitly model PCET in condensed phases.
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    Simulating biochemical physics with computers
    (2010-08) Lin, Pinsker Yen-lin
    This dissertation is composed of three parts. The first part is to argue the solvent effects on the solvatochromic shift of the n ! !* excitation of acetone in ambient and supercritical water fluid using a hybrid QM!CI/MM potential in MC simulations. The solute is described by the AM1 approach and water molecules are treated classically. Specially, the spontaneous polarization of the solvent due to the excitation of the solute was considered. The solvent effects on the blue shift of acetone in water fluids at various temperatures and solvent densities are examined. The second part is to investigate the role of dopa decarboxylase (DDC) in the catalysis of converting anti-Parkinson drug L-dopa into dopamine. By means of combined QM/MM potentials in MD simulations, we first analyze the factors contributing to the tautomeric equilibrium of an intramolecular proton transfer in the external PLP!L-dopa aldimine (the Michaelis complex). How the intrinsic properties, solvent effects as well as the enzyme environment control the shift of the equilibrium is discussed. Afterward, the free energy profiles for the decarboxylations of the external aldimines both in water and in DDC are calculated. The contributions of DDC to the rate enhancement of the reaction are elucidated. The reaction mechanism of L-dopa decarboxylation in DDC is proposed. The third part is to study the structural dynamics of lysine-specific demethylase (LSD1) in complex with CoREST and protein-substrate interactions of LSD1 with histone H3 tail. MD simulations of LSD1•CoREST complex bound to a 16 a.a. of the Nterminal H3-tail peptide (H3-p16) were carried out using NAMD to study the conformational flexibility of the protein complex, especially the substantial oscillation of the TOWER domain. In addition, the simulations reveal some important protein-peptide and peptide-peptide interactions between LSD1 and H3-p16 that are absent in the crystal structure.