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Flexibility vs. preorganization: molucular simulations of MDM2-p53 peptide binding events

Wang, David Wen Rui (2012) Flexibility vs. preorganization: molucular simulations of MDM2-p53 peptide binding events. Undergraduate Thesis, University of Pittsburgh. (Unpublished)

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Speeding the molecular binding process is of particular interest in many fields. While traditional belief dictates that ligand preorganization is optimal, the discovery of intrinsically disordered proteins may contest such convention. The “fly-casting” mechanism argues that a flexible protein can bind its partner faster due to a larger capture radius and a resulting coupled process of folding and binding. We directly test this hypothesis, using computational means, on the p53-MDM2 system, performing binding simulations of MDM2 to either a flexible p53 peptide or its exact preorganized analog. We employ a path sampling algorithm, weighted ensemble, to generate large ensembles of binding pathways and to calculate rates of association. Additionally, the effect of hydrodynamic interactions, often omitted in implicit solvent simulations, on the binding rates was examined. We find no difference between the binding rates of flexible p53 and preorganized p53. The exclusion of hydrodynamic interactions significantly decreases the binding rates due to largely reduced translational diffusion coefficients, indicating the importance of using hydrodynamic interactions in binding simulations.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Wang, David Wen Ruidaw88@pitt.eduDAW88
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorChong, Lillian T.ltchong@pitt.eduLTCHONG
Committee MemberSwigon, Davidswigon@pitt.eduSWIGON
Committee MemberZuckerman, Daniel M.ddmmzz@pitt.eduDDMMZZ
Committee MemberPlaxco, Kevin
Date: 25 May 2012
Date Type: Publication
Defense Date: 12 April 2012
Approval Date: 25 May 2012
Submission Date: 17 April 2012
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Number of Pages: 36
Institution: University of Pittsburgh
Schools and Programs: University Honors College
Dietrich School of Arts and Sciences > Chemistry
Degree: BPhil - Bachelor of Philosophy
Thesis Type: Undergraduate Thesis
Refereed: Yes
Uncontrolled Keywords: computer simulations, p53-MDM2, weighted ensemble, flexibility vs preorganization, hydrodynamic interactions
Date Deposited: 25 May 2012 19:47
Last Modified: 25 May 2017 05:15


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