Abstract
Biological membranes are crucial components of all cells. They are bilayer mixtures composed by various types of lipids and a large number of membrane proteins. The latter, based on their position with respect to the membrane plane, are classified into transmembrane, peripheral membrane and lipid-anchored proteins. Transmembrane proteins constitute approximately 25-30% of known proteomes and control a wide range of cell functions, ranging from signal transduction and substrate transport to maintaining cell integrity and the regulation of gene expression, cell growth and cell death. As a result, transmembrane proteins have been implicated in a wide range of diseases and constitute prime targets in drug design. An important part of transmembrane protein functionality is their capability to form protein-protein interactions. The formation of supramolecular protein-protein complexes in the membrane plane, either between two or more transmembrane proteins or between transmembrane and ...
Biological membranes are crucial components of all cells. They are bilayer mixtures composed by various types of lipids and a large number of membrane proteins. The latter, based on their position with respect to the membrane plane, are classified into transmembrane, peripheral membrane and lipid-anchored proteins. Transmembrane proteins constitute approximately 25-30% of known proteomes and control a wide range of cell functions, ranging from signal transduction and substrate transport to maintaining cell integrity and the regulation of gene expression, cell growth and cell death. As a result, transmembrane proteins have been implicated in a wide range of diseases and constitute prime targets in drug design. An important part of transmembrane protein functionality is their capability to form protein-protein interactions. The formation of supramolecular protein-protein complexes in the membrane plane, either between two or more transmembrane proteins or between transmembrane and non-transmembrane proteins, is an integral part of their canonical function. At the same time, a large number of transmembrane protein complexes have been implicated with several diseases. Despite their importance, however, the experimental study of transmembrane proteins and their interactions is not straightforward. The aim of this dissertation is the computational study of protein-protein interactions in biological membranes and transmembrane proteins. Towards this end, an extensive study of protein – protein interactions was conducted for several transmembrane proteins, both at the structural level, through Molecular Modeling, Molecular Dynamics simulations and Free Energy calculations, and in a system-wide approach, through the application of concepts from Network Theory. Alongside protein – protein interactions, the structural and dynamic aspects of the membrane environment were also investigated, in order to identify and evaluate the structural determinants that govern the lipid bilayer’s influences upon transmembrane protein structure and biomolecular interactions. Finally, during the course of this study, a number of publicly available, computational tools were developed, which can further aid in the study of biological membranes, transmembrane proteins and their interactions. The aforementioned studies were conducted both for transmembrane proteins located at the plasma membrane of eukaryotic cells, such as G-protein coupled receptors (GPCRs) and Receptor Tyrosine Kinases (RTKs), and for proteins found in other cell components, such as the Outer Membranes of Gram-negative bacteria and transmembrane β-barrels, as well as the double membrane system of the Nuclear Envelope and its proteins. The results of this dissertation can be applicable in the further study of protein-protein interactions in transmembrane proteins, both through experimental and through computational approaches.
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