David M. Ferguson, Fellow

Simulation of Hairpin Loop Structures Using Molecular Dynamics; Modeling of Opioid Drug/Receptor Interactions

This group studies the structure, function, and dynamics of macromolecules and macromolecular interactions using a variety of computational techniques. These include molecular graphics, empirical force fields, ab initio calculations, molecular docking, and molecular dynamics simulations. A primary emphasis of this work focuses on the development and application of structural models of G-protein-coupled receptors (GPCRs) to ligand design. In particular, the researchers were concerned with developing highly selective opioid ligands with modified pharmacological properties. A second area of emphasis was placed on studying the structure, dynamics, and thermodynamic stability of modified nucleic acid complexes for use in antisense drug development. Both projects required significant force field parameterization, ab initio model calculations, and long time-scale molecular dynamics simulations, as well as graphics visualizations with the long-term goal of modeling molecular recognition processes reliably and confidently for use in drug design and development.

This group developed research on the conformations landscape of selective µ-opioid agonists in gas phase and in aqueous solution (the fentanyl series). Here, the conformational characteristics responsible for high affinity-opioid binding of a series of fentanyl analogs were investigated using a combination of molecular mechanics and molecular dynamics techniques. In general, the fentanyl analogs favor a conformation that is quite different in gas phase, and in the presence of explicit solvent or lattice packing forces. The most active analogs were shown to possess an extended conformation, while fentanyl derivatives displayed reduced binding affinities are predicted to favor compact arrangements. A superposition of the proposed “bioactive conformations” across this ligand series identified the orientation of the Nphenethyl and the N-phenyl group to be a contributing factor responsible for the differential bind of the ohmefentanyl enantiomers, and other structural analogs. The 3-point pharmacophore model for the fentanyls also provided insights into the structure-activity relationship and served as a template for further QSAR and docking studies.

Deoxyribonucleic acid (DNA) hairpin loops are vulnerable spots on the DNA and play an important role in the control of several important biological functions. Such DNA molecules are intermediates in cellular processes in which they are opened by enzymes—nucleases—to produce short single stranded extensions. It has been shown that this enzyme recognition is not entirely dependent on the sequence of the hairpin loop but is also believed to be dependent on the structure of the hairpin loop. Using molecular dynamics (MD) simulations, the researchers addressed the question of whether the pattern of DNA hairpin opening by nucleases is dependent on the structural features of the hairpin loop. Observations from previous NMR studies have shown that the palindromic duplex sequence 5´d(CFCFTATATACFCF)3´ is a dimer at lower temperatures and forms a hairpin loop structure at higher temperatures. Hence, the team studied this DNA hairpin loop structure using the amber code modules; they will analyze the structures obtained from their simulations in light of the available NMR data. Based on the MD simulations, the researchers can correlate the structural features of the hairpin loop to the nuclease digestion pattern that will provide new insights into the mechanism of DNA hairpin cleavage by nucleases.

Research Group

John Goodell, Graduate Student Researcher
Brian Kane, Graduate Student Researcher
Mahadevan Seetharaman, Graduate Student Researcher