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Open Access Publications from the University of California

Noncovalent Interactions: Evaluation of computational methods and characterization of molecular binding

  • Author(s): Li, Amanda
  • Advisor(s): Gilson, Michael K
  • Huang, Xiaohua
  • et al.
Abstract

Noncovalent interactions are of central importance to biochemical phenomena. This dissertation includes both evaluations of the methods used to compute noncovalent interactions and analyses of their role in binding. First, various QM approaches for calculating noncovalent interaction energies are compared in over 1,200 gas-phase dimers. In particular, we study semiempirical PMx methods, density functional theory (DFT) approaches, and symmetry-adapted perturbation theory (SAPT). Linearly scaled SAPT0 (fSAPT0) methods are fitted and shown to yield high accuracy, at particularly low computational cost. Additionally, various models of polarization are examined for their ability to reproduce perturbed electrostatic potentials (ESPs). Polarization models are broken down into two main components: the representation of electronic polarization, and the response model used to map from an inducing field to the polarization within the chosen representation. The results reveal that the inducible dipole models used in many current polarizable force fields fall far short of the optimal results in principle achievable by the atom-centered point dipole representation. Lastly, binding interactions are examined between heteroallene-containing guests and cucurbituril host systems using quantum calculations and in Grb2 SH2 complexes using molecular dynamics simulations. For the host-guest systems, the heteroallenes are shown to exhibit attractive interactions with the carbonyl oxygens of the host, and these interactions are found to be primarily electrostatic and dispersive in nature. For the Grb2 SH2 domain, the thermodynamics of ligand preorganization are studied by computing relative binding enthalpies for flexible and constrained ligands.

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