Part I: Structure and function in the NMDA ligand binding domain. Part II: Comparison of paclitaxel analogs through molecular dynamics simulation; solution conformations of cyclic peptides

Part I. The NMDA receptor is an ionotropic glutamate receptor found throughout the CNS. The receptor functions as a tetramer comprised of two NR1 subunits and two NR2 subunits. There are four subtypes of NR2, NR2A through NR2D, and functional properties of the assembled receptor vary with the identity of the NR2 subunits. The ligand binding domain of this receptor binds either the agonist glutamate or co-agonist glycine, and triggers the gating process which allows ions to flow through the channel. Crystal structures of the ligand binding domain have recently been solved, and these structures provided the basis for molecular dynamics simulations of ligand binding domains of different NR2 subtypes. Structures of different NR2 ligand binding domains were prepared by homology modeling, and simulations were performed of just the NR2 ligand binding domain, as well as simulation of the ligand binding domain dimer of NR1/NR2. Comparison of simulations of different subtypes as well as the same subtype with different ligands bound reveal structural differences and changes that may shed light on how the receptor functions.;Part II. The dynamic equilibrium between free alpha,beta-tubulin and assembled microtubules plays a important role in cellular structure. Alteration of this equilibrium by paclitaxel (PTX) and other similar compounds is a critical method of anti-cancer treatment, and recently analogs were discovered that induce polymerization at levels much greater than paclitaxel. These analogs were placed into a crystal structure of alpha,beta-tubulin with PTX and subjected to molecular dynamics simulation. Over the simulation the analogs induced changes in the critical M-loop and strengthened theories of how the M-loop facilitates tubulin polymerization.;A cyclic pentapeptide was analyzed using NAMFIS (NMR Analysis of Molecular Flexibility In Solution), a method which combines NMR data and modeling-based conformational searching. This peptide was well-studied in the literature, providing an opportunity to evaluate NAMFIS alongside other methods for predicting conformations of small molecules in solution. NAMFIS was able to identify the conformations previously found, as well as a few new conformations that may be necessary to recreate the NMR data accurately.