G-protein-coupled receptors are of great pharmaceutical interest, comprising the majority of targets for currently marketed drugs. The theme of my thesis is the development of the structure prediction method, MembStruk, for the superfamily of G-protein-coupled receptors. The first part of this thesis focuses on the methods and their validation. There are several steps involved in MembStruk that are detailed and tested for membrane proteins with known structures in the first few chapters (Chapters 2-6). Specifically, the first principles methods for predicting the transmembrane helical ranges and the helix hydrophobic centers are tested. The program for predicting the transmembrane helical ranges, TM2ndS, ranks in the top two when comparing performance with other top prediction methods. And because it is based on general principles, it can be applied robustly for membrane protein families for which little structural information is available. The simulation of the EC-II closing is also tested on bovine rhodopsin. The use of the MembStruk method on bovine rhodopsin as a validation case is presented in detail (Chapter 2). The large majority (71%) of the residues involved in binding in rhodopsin are predicted and the protein structure itself is 2.84 [...] coordinate root mean square error in the transmembrane main chain atoms from the crystal structure.The second part of the thesis discusses applications on various G-protein-coupled receptor systems. The application of the MembStruk method to other peptide chemokine G-protein-coupled receptors like CCR1 and CCR5 is discussed in Chapter 9. The fundamental scientific problems of G-protein-coupled receptor modulation of absorption and relaxation properties of a bound chromophore (retinal) are addressed and results are presented for the predictions of these properties.The prediction of structure and function of G-protein-coupled receptors would allow for structure-based drug design and a rational approach to reducing drug cross-reactivity across receptor families.
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