Development and Application of OPLS Force Fields for Modeling Protein-Ligand Interactions [electronic resource].

9780438902602

Ann Arbor : ProQuest Dissertations & Theses, 2018.

1 online resource (182 p.)

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First, a new octahedral site model is designed for representing divalent metal ions in condensed phases. In biomolecular simulations, divalent metal ions are often represented using either a bonded model or a non-bonded soft sphere model. The former model often suffers from poor transferability, rigid coordination sphere and insufficient sampling, whereas the latter suffers from the inability to model the polarizability, charge-transfer and coordination effects of metal ions. Multi-site model such as octahedral site (Oh) model has been devised for metal ions to overcome these problems. In the current study, a three-step methodology is presented to obtain force field parameters for Oh model for 10 biologically relevant divalent metal ions in TIP3P and TIP4P water models. These parameters demonstrate transferability and are designed to reproduce free energies of hydration, radial distribution functions and coordination numbers within 2% of experimental data, providing a complete description for structure and energetics of ionic hydration. The applicability of CM5 charges is investigated for use in non-aqueous condensed phase simulations. Partial atomic charges for neutral molecules from quantum mechanical calculations are typically scaled for use in molecular modeling of liquid-phase systems. Optimal scale factors of 1.14 for CM1A and 1.27 for CMS charges were previously determined for minimizing errors in free energies of hydration. The adequacy of the 1.14*CM1A and 1.27*CM5 models are evaluated here for pure liquid simulations in combination with the OPLS-AA force field. For 22 organic liquids, the 1.14*CM1A and 1.27*CM5 models yield mean unsigned errors (MUEs) of ca. 1.40 kcal/mol for heats of vaporization. Not surprisingly, this reflects over-polarization with the scale factors derived for aqueous media. Prediction of pure liquid properties using CM5 charges is optimized using a scale factor of 1.14, which reduces the MUE for heats of vaporization to 0.89 kcal/mol. However, due to the impracticality of using different scale factors in different explicit-solvent condensed phase simulations, a universal scale factor of 1.20 emerged for CM5 charges. This provides a balance between errors in computed pure liquid properties and free energies of hydration. Computation of free energies of hydration by the GB/SA method further found that 1.20 is equally suited for use in explicit or implicit treatments of aqueous solvation. With 1.20*CM5 charges, a variety of condensed-phase simulations can be pursued while maintaining average errors of 1.0 kcal/mol in key thermodynamic properties. The quality of the 1.14*CM1A and 1.20*CM5 charge models was evaluated for calculations of free energies of hydration. For a set of 426 neutral molecules, 1.14*CM1A and 1.20*CM5 yield MADs of 1.26 and 1.20 kcal/mol, respectively. The 1.14*CM1A charges, which can be readily obtained for large systems, exhibit large deviations only for a subset of functional groups. The results for these cases were systematically improved using Localized Bond Charge Corrections (LBCC) by which off-setting adjustments are made to the partial charges for atoms in specified bond types. Only 19 LBCCs were needed to yield 1.14*CM1A-LBCC charges that reduce the errors for the 426 ΔGhyd values to only 0.61 kcal/mol. The modified charge method was also tested in computation of heats of vaporization and densities for pure organic liquids, yielding average errors of 1.40 kcal/mol and 0.024 g/cm3, similar to those for 1.14*CM1A. Despite the progress made in force fields, small molecule parameterization remains an open problem due to the magnitude of the chemical space; the most critical issue is the estimation of a balanced set of atomic charges with the ability to reproduce experimental properties. To make the 1.14*CM1A(-LBCC) charges generation more accessible, LigParGen server and command line program is designed and implemented. The LigParGen web server provides an intuitive interface for generating OPLS- AAl1.14*CM1A(-LBCC) force field parameters for organic ligands, in the formats of commonly used molecular dynamics and Monte Carlo simulation packages. This server has high value for researchers interested in studying any phenomena based on intel molecular interactions with ligands via molecular mechanics simulations. It is free and open to all at jorgensenresearch.com/ligpargen, and has no login requirements. Non-nucleoside reverse transcriptase inhibitors (NNRTI) target HIV-1 infections by binding to an allosteric binding pocket of HIV-1 reverse transcriptase protein far from the transcriptase site. Because of the low barrier for genetic mutation, it is easy for the HIVRT to mutate and develop resistance for the existing NNRTIs. Therefore the continuous development of novel NNRTIs is needed. For designing novel NNRTIs, it is of fundamental importance to understand the exit pathway of NNRTI from the binding pocket, and the role played by binding pocket residues in binding/unbinding dynamics of NNRTI. Metadynamics simulations are performed to study how the JLJ135 unbinds and to understand the role of binding pocket residues in stabilizing various steps of the unbinding pathway. A general and transferable collective variable (CV) defined by the distance between the center of mass (COM) of the binding pocket and COM of the ligand is proposed for studying unbinding dynamics. This CV is further applied to successfully in rank a congeneric series of ligands as per their cellular activity (EC50).

Dissertations & Theses @ Yale University.

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English

August 21, 2019

Thesis (Ph.D.)--Yale University, 2018.

Yale University.