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Reference: Worth, Graham Alan., (1992). The energetics of nucleotide binding to RAS proteins. DPhil. University of Oxford.Citable link to this page:

 

The energetics of nucleotide binding to RAS proteins

Abstract: Ras proteins are a special class of proteins that mediate cell growth signals. Theirimportance lies in the fact that they are products of a proto-oncogene. This means thatunder certain conditions the gene that determines its structure is altered and a mutantprotein results that is involved in the transformation of normal cells to cancer cells.The actual function by which the protein acts in the signal pathway is not known.However it is known that they act as a switch, undergoing a cycle involving the exchangeof guaninosine nucleotides in the binding site. This thesis uses computer simulations tostudy the energetics of this binding, with the long term aim of developing a drug to inhibitthe transforming activity of the oncogenic protein.To begin with, a model of the protein based on a crystal structure is built. UsingMolecular dynamics the motion of this model is studied. A possible mechanism by whichone half of the nucleotide cycle could be induced is investigated, with the result thatphosphorylation of the protein may be involved.The main part of the thesis is then devoted to using the free energy perturbation(FEP) method to calculate the difference in Gibbs binding free energy between thenucleotides in the protein.Using histamine as a model, a method of dealing with charged, flexible moleculesis developed; namely the inclusion of a reaction field and comprehensive conformationalanalysis. The results from the associated calculations are seen to be very close toexperimental data. The same procedures are then applied to the much more complex ras:nucleotide system with less successful results, the reason for which is mostly due to therestriction of limited computer resources to tackle such a problem.The conclusion is that given the resources and by using the techniques developed inthis thesis, this type of calculation is a feasible way to study such systems.

Type of Award:DPhil Level of Award:Doctoral Awarding Institution: University of Oxford Notes:The digital copy of this thesis has been made available thanks to the generosity of Dr Leonard Polonsky

Contributors

Richards, W. G. (William Graham)More by this contributor

RoleSupervisor

 

Dr. Graham RichardsMore by this contributor

RoleSupervisor

 Bibliographic Details

Issue Date: 1992Identifiers

Urn: uuid:44524415-2f2b-4601-998c-56110f332153

Source identifier: 603840939 Item Description

Type: Thesis;

Language: eng Subjects: Nucleotides Proteins Cells Growth Tiny URL: td:603840939

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Autor: Worth, Graham Alan. - institutionUniversity of Oxford facultyMathematical and Physical Sciences Division - - - - Contributors Ric

Fuente: https://ora.ox.ac.uk/objects/uuid:44524415-2f2b-4601-998c-56110f332153



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