eprintid: 11867 rev_number: 16 userid: 836 dir: disk0/00/01/18/67 datestamp: 2012-05-25 19:47:19 lastmod: 2017-05-25 05:15:04 status_changed: 2012-05-25 19:47:19 type: thesis_degree metadata_visibility: show contact_email: davidwang38@gmail.com item_issues_count: 0 eprint_status: archive creators_name: Wang, David Wen Rui creators_email: daw88@pitt.edu creators_id: DAW88 title: Flexibility vs. preorganization: molucular simulations of MDM2-p53 peptide binding events ispublished: unpub divisions: sch_uhc divisions: sch_as_chemistry full_text_status: public keywords: computer simulations, p53-MDM2, weighted ensemble, flexibility vs preorganization, hydrodynamic interactions abstract: 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. date: 2012-05-25 date_type: published pages: 36 institution: University of Pittsburgh refereed: TRUE etdcommittee_type: thesis_advisor etdcommittee_type: committee_member etdcommittee_type: committee_member etdcommittee_type: committee_member etdcommittee_name: Chong, Lillian T. etdcommittee_name: Swigon, David etdcommittee_name: Zuckerman, Daniel M. etdcommittee_name: Plaxco, Kevin W. etdcommittee_email: ltchong@pitt.edu etdcommittee_email: swigon@pitt.edu etdcommittee_email: ddmmzz@pitt.edu etdcommittee_email: kwp@chem.ucsb.edu etdcommittee_id: LTCHONG etdcommittee_id: SWIGON etdcommittee_id: DDMMZZ etdcommittee_id: etd_defense_date: 2012-04-12 etd_approval_date: 2012-05-25 etd_submission_date: 2012-04-17 etd_release_date: 2012-05-25 etd_access_restriction: 5_year etd_patent_pending: FALSE assigned_doi: doi:10.5195/pitt.etd.2012.11867 thesis_type: undergradthesis degree: BPhil citation: Wang, David Wen Rui (2012) Flexibility vs. preorganization: molucular simulations of MDM2-p53 peptide binding events. Undergraduate Thesis, University of Pittsburgh. (Unpublished) document_url: http://d-scholarship-dev.library.pitt.edu/11867/1/Wang_David_BPhil_ETD.pdf