Computational studies of biological molecules

Computer-based molecular modelling techniques can give great insight into the structure and function of biological molecules, particularly as part of a multi-disciplinary study. In this thesis, three applications are presented: 1. Integrins are involved in a wide variety of adhesion-related processes. Models of the integrin p3 subunit were produced, to investigate the proposal that this region adopts a similar three-dimensional structure to that of the I-domain of certain integrin a subunits (which contains the unique Metal Ion-Dependent Adhesion Site - MIDAS). Site-directed mutagenesis experiments (performed by collaborators) identified functionally important residues. The resulting models suggest that this region of p3 may indeed adopt a similar, but not identical, conformation to the a subunit MIDAS domain - and provide further information on the nature of integrin-ligand interactions. 2. Glutamate receptors are the primary excitatory neurotransmitter receptors in vertebrate brain. Structural models of glutamate receptors were produced as part of a multi-disciplinary study of neuronal function - both ligand/receptor interactions and ion transport - at the atomic level. The models have concentrated on the agonist binding and transmembrane domains of ionotropic (i.e. ligand- gated) glutamate receptors (iGluRs), and, by studying a variety of agonists and antagonists, details have been built up of (i) those residues involved in ligand binding and (ii) the role of agonist binding (i.e. agonist-induced conformational change) in channel gating. The conductance properties of the channels were also investigated, and the models found to be consistent with (and provide possible explanations for) experimentally-observed behaviour. 3. Nuclear magnetic resonance (nmr) spectroscopy data (obtained by collaborators) were used to study the solution structure of the polyene antibiotic Amphotericin B (a widely used treatment for fungal infections). The results shed new light on the self-associated structure of the molecule in solution, and provide some possible insight into the observed high toxicity of this important pharmaceutical.