Molecular dynamics of nuclear PPARg receptors: ligand dissociation mechanisms

Abstract

Nuclear hormone receptors form an important family of trascription factors. They are DNA-binding proteins, and are regulated by the binding of hormones (Estrogen, Thyroid Hormone, Retinoic Acid, among others). The specific binding to DNA and regulated hormone binding determine whether a gene will be transcripted or repressed. Since 1995 several three-dimensional structures of the LBD of nuclear receptors were obtained, allowing for important advances in the comprehension of the molecular biology of hormone recognition. However, in spite of the fact that new structures were obtained for different receptors, the role of the dynamics of the receptors remained fundamentally unknown.In this project we propose the study of the dynamics of nuclear hormone receptors and their role in the biological function of these proteins using Molecular Dynamics simulations. The Skaf group has obtained results that associate the dynamics of the receptors to their function in various different areas, such as hormone binding and dissociation, ligand selectivity and denaturation mechanisms, for example.The use of new techniques for expanding these results may complement our studies in a important way, leading to one of the most comprehensive set of data on the dynamics of nuclear hormone receptors. Three main new areas of research are proposed in the present project:1. Analysis of the interactions between PPARg and natural and synthetic ligands.2. Investigation of likely ligand dissociation pathways from PPARg.3. Evaluation of the relative importance of putative dissociation pathways and detailed ligand release molecular mechanisms.