• The use of conformational sampling in CHARMM protein force field optimization and ligand-based drug design

      Shim, Jihyun; MacKerell, Alexander D., Jr. (2013)
      Sampling of the conformational space of biomolecules in computer simulations allows researchers to investigate atomistic details of biological phenomena such as protein folding and ligand binding. Conformational sampling based on empirical energy functions depends on the force field and is aided by enhanced simulation methods. This thesis discusses conformational sampling methods and force fields, along with application of conformational sampling to force-field optimization and ligand-based drug design. Extensive conformational sampling was performed for small peptides and drug-like molecules using temperature replica-exchange and Hamiltonian replica-exchange molecular dynamics. Obtained conformational ensembles were then used to improve peptide-backbone and side-chain parameters in the CHARMM protein force fields, thereby yielding more accurate conformational properties. Obtained ensembles were also applied to ligand-based drug design where a novel method based on the conformationally sampled pharmacophore approach was used to identify quantitative structure-activity relationships (SARs) of μ opioid receptor ligands. Based on the SARs, we proposed ligand-binding orientations related to receptor activation. The binding orientations were further investigated using simulations of selected ligands bound to the 3-dimensional -opioid receptor structures. Our studies validate ligand-based SARs and show atomistic details of ligand-receptor interactions and the mechanism of µ opioid receptor activation.