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Title: Computational study of dually phosphorylated peptides binding to the SRC SHZ domain
Author: Geroult, Sebastian Claude Robert
ISNI:       0000 0004 2669 4151
Awarding Body: Birkbeck (University of London)
Current Institution: Birkbeck (University of London)
Date of Award: 2008
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The binding of tyrosine phosphorylated targets by SH2 domains is required for the propagation of many cellular signals in higher eukaryotes. In this thesis we studied computationally the bindings of Src SH2 domain to Ac-PQpYEpYIPI-NH2 and Ac- PQpYIpYVPI-NH2, two dually-phosphorylated ligands, and their interfacial water molecules. Structures of SH2 domains with bound ligands indicate a potentially important role of water in influencing binding thermodynamics. We have investigated the role of interfacial water molecules on the prediction of the thermodynamics of SH2 domain "" binding to phosphopeptides using a method based on accessible surface area buried upon association. We show that the model does not predict the binding thermodynamics of either ligand. However, we identified the empirical formula describing the heat capacity change values as falling from 0 to -300 cal/mol.deg results in a sharp distribution of the number of ligandlSH2/water-subset structures that provide binding thermodynamics similar to experimental values. This prompted us to experimentally determine the heat capacity change for each of the peptides and we found them to coincide with the values of the peaks. We next used molecular dynamics (MD) simulation methods to evaluate solvation sites at the binding interface of the Src SH2 domain. We showed that the method computed the first water shell of the protein and predicted the crystallographic water molecules positions at 50 to 80% within a distance of 0.9 angstroms, on average. Comparison of the simulated water structures of both the bound and unbound binding partners led to a thorough evaluation of water behaviour during the binding reaction. We also showed that the simulated water structures of all ligandlSH21 domain structures investigated here can be used to accurately derive the binding heat capacity change using a method based on accessible surface area buried upon association. Finally, we studied the interfacial solvation energetic landscapeof structures of the Src SH2 domain bound to three dually phosphorylated ligands, and investigated the difference in the energetic landscape of the bound complexes. We have found that the energy change in the thermodynamic signature difference between Ac-PQpYEpYIPI-NH2 and Ac-PQpYlpYVPI-NH2 binding is due to the combination of small structural rearrangements in the position of protein's and ligand's residues resulting in a higher flexibility of the +2 phosphotyrosine. The insights gained into the binding event from these simulation experiments lead to a better understanding of the role of water in influencing the binding thermodynamics.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available