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Molecular docking algorithms are computational methods that predict the binding site and docking pose of specified ligands with a protein target. They have proliferated in recent years, due to the explosion of structural data in biology. Oxdock is an algorithm that uses various techniques to simplify this complex task, the most significant being the use of a multiscale approach to analyse the problem using a simple representation in the early stages. Oxdock is shown to be a very useful tool in computational biology, as exemplified by two cases. The first case is the analysis of the NMDA subclass of neuronal glutamate receptors and the subsequent elucidation of their function. The second is the investigation of the newly discovered plant glutamate receptors and the clarification of their natural ligands. The results in both instances open new areas of research into exciting areas of biology. Despite its effectiveness in solving many problems, Oxdock does fail in a number of circumstances. It is thus important to devise a new and improved method for molecular docking. This is achieved by combining the speed of the multiscale approach with the optimising ability of Evolutionary Programming. This yields an algorithm that is shown to be precise, accurate and specific. The new algorithm, Eve, is then modified to illustrate its potential in both lead optimisation and de novo drug design. These capacities, combined with its ability to predict the location of binding sites and the docking pose of a ligand, highlight the promise of computational methods in solving problems in many areas of biological chemistry.

Partial cDNAs for each of the four known N-methyl-D-aspartate (NMDA) receptor 2 (NMDAR2A-D) subunits have been cloned from the brain of A. leptorhynchus and are found to display a high degree of sequence homology (83--78% amino acid identity) to their mammalian homologues. In situ hybridization experiments reveal that each transcript has a distinct expression pattern in the apteronotid central nervous system (CNS) and is present in a "mosaic" distribution within important cell types of the electrosensory lateral line lobe (ELL). Apt. NMDAR2A transcript is expressed in forebrain regions as well as throughout the pyramidal cell layer (PCL) and granule cell layer (GCL) of the ELL. Apt. NMDAR2B mRNA is enriched in mid- and forebrain structures as well as the PCL and GCL of the ELL. Apt. NMDAR2C transcript is largely restricted to cerebellar regions but is also found in the PCL and GCL of the ELL's medial, centromedial, and centrolateral segments. Apt. NMDAR2D mRNA is expressed in sites of cell proliferation and in a segmental gradient within granule cells of the ELL.

Memory of some forms requires the hippocampus, a brain structure in the medial temporal lobe that reveals remarkable synaptic plasticity. Most synapses in the hippocampus require NMDA-receptors for the induction of this plasticity. Memories that require the hippocampus may also require NMDA-receptor mediated plasticity. This thesis tested the involvement of NMDA receptor activity in memory for a non-spatial, social learning task that requires the hippocampus: the social transmission of food preference, NMDA receptor antagonist (CPP) injected systemically 55 minutes prior to training impaired performance 72 hours later, but not 48 hours, 24 hours, or 15 minutes later. NMDA receptor antagonist (AP-5) injected into the dorsal hippocampus 30 minutes prior to training also impaired performance at the 72-hour delay. Injections of CPP at 10 minutes or 24 hours post-training had no effect on performance. These results suggest that hippocampal NMDA receptor activity is necessary for stable learning of the non-spatial social transmission of food preference.

N-methyl-D-aspartate (NMDA) receptor activation is believed necessary for certain types of learning. The present experiments investigated the effects of the NMDA antagonist, MK-801, on spatial learning and memory in rats. Experiment 1 tested the effects of MK-801 on the acquisition and retention of a water maze task. MK-801 produced a performance, but not a spatial learning deficit. Experiment 2 tested the effects of MK-801 on the acquisition and retention of a radial arm maze task (RAM). MK-801 had no effect on initial acquisition and retention, but impaired subsequent reversal learning when the pattern of rewarded and unrewarded arms was reversed. Experiment 3 investigated the effects of MK-801 on RAM reversal learning in rats previously trained on the initial task in the absence of drugs. MK-801 produced a dose dependent impairment on reversal learning. These results are consistent with one interpretation that MK-801 impairs the ability to suppress interference from previously learned information.

Declarative learning entails the internalization of facts and events. This type of learning depends on the integrity of the hippocampal system. In rodents, spatial learning is studied as a model of declarative learning. In this thesis, electrophysiological and behavioral experiments assessed the role of NMDA receptors in synaptic plasticity and rats' spatial learning and memory. Primed burst potentiation (PBP), a form of synaptic strengthening, was studied in freely-behaving rats treated with NMDA receptor antagonists. The impairments caused by the antagonists correlated with those observed in behavioral studies. The results support the idea that NMDA receptors in the hippocampal system mediate the internalization of the contents and organization of new environmental information, and show that the receptors are not relevant for spatial working memory or performance once a representation of the environment is stable. The results also suggest that stable spatial representations resemble multiple relations of events and do not correspond to topographical maps of an environment. As learning proceeds, representations are activated by smaller subsets of environmental cues, which eventually become sufficient for effective navigation. The representations thus are encoded as relationships of stimuli that share similarities or that are unique to a particular event. The organization of novel information is given through NMDA receptor-mediated synaptic plasticity. This plasticity mechanism could resemble a process similar to the synaptic changes observed during PBP.

Thesis (Ph. D.)--Carleton University, 2004. / Includes bibliographical references (p. 118-146). Also available in electronic format on the Internet.

Thesis (M.A.)--University of North Carolina Wilmington, 2009. / Title from PDF title page (January 12, 2010) Includes bibliographical references (p. 111-113)

Thesis (M.A.)--University of North Carolina Wilmington, 2009. / Title from PDF title page (January 11, 2010) Includes bibliographical references (p. 63-68)