Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.435198
Title: Exploration of the conformational energy landscape of small peptides using electronic structure methods
Author: Toroz, Dimitrios
ISNI:       0000 0001 3535 3162
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2006
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Abstract:
Small peptides work as neurotransmitters or hormones in the body. For example, the pentapeptide enkephalin is involved in a wide variety of physiological processes such as mediation of pain and respiratory depression. In order to understand the biological function of these molecules it is necessary to examine their molecular shape and structural preferences. The large flexibility of peptides makes them difficult to be characterized by experimental and theoretical methods. A method was developed in order to explore the conformational preferences of a polypeptide using electronic structure methods based on hierarchical selection criteria. The strategy was to vary all the torsion angles of the peptide and to create all possible conformers. The conformers were assessed according to the number of hydrogen-bonding interactions in their structure. Calculations were performed at increasingly higher levels of theory. Only a number of the most stable conformers were taken through to the next level. This hierarchical selection method was used to explore the conformational features of the dipeptide Tyr-Gly (the first two amino acids of the pentapeptide enkephalin: Tyr-Gly-Gly-Phe-Met).The conformational preferences of Tyr-Gly were also explored with a stepwise rotation method. The hierarchical selection method seemed to be superior. The most stable conformers found for Tyr-Gly are characterized by a characteristic hydrogen-bonding interaction (0-H 0) between the hydroxyl hydrogen of glycine and the carboxyl oxygen of tyrosine. The optimized structures obtained with DFT differ from the structures obtained by MP2 geometry optimizations. MP2 optimizations make the structures more folded. The method has also been used to study the conformational features of the Tyr- Gly-Gly tripeptide, Tyr-Gly-Gly-Phe tetrapeptide, Tyr-Gly-Gly-Phe-Leu pentapeptide and Gly-GIy-Gly tripeptide. The most stable conformers obtained for the Tyr-Gly-Gly tripeptide are characterized by folded structures with a characteristic hydrogen-bonding interaction between the (-OH) phenyl group of tyrosine and the carboxyl oxygen of glycine (3). The most stable conformers obtained for Tyr-Gly-Gly-Phe and Tyr-Gly-Gly-Phe-Leu are characterized by folded structures with a characteristic hydrogen-bonding interaction between the (-OH) phenyl group of tyrosine and the carboxyl oxygen of phenylalanine (4). For Tyr-Gly, Tyr-Gly-Gly, Tyr-Gly-Gly-Phe and Tyr-Gly-Gly-Phe-Leu a large variation has been observed between DFT and MP2 orders of stability of the conformers. DFT fails to describe the dispersion effects arising from interactions involving the aromatic residues. MP2 would probably describe more accurately the conformational preferences of these peptides. However, the large basis set superposition error in MP2 calculations means that also MP2 may not be suitable to characterize the conformational preferences of these peptides. The hierarchical selection method developed has been shown to be a useful method to study small peptides.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.435198  DOI: Not available
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