?url_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Adc&rft.relation=http%3A%2F%2Fd-scholarship-dev.library.pitt.edu%2F11867%2F&rft.title=Flexibility+vs.+preorganization%3A+molucular+simulations+of+MDM2-p53+peptide+binding+events&rft.creator=Wang%2C+David+Wen+Rui&rft.description=Speeding+the+molecular+binding+process+is+of+particular+interest+in+many+fields.+While+traditional+belief+dictates+that+ligand+preorganization+is+optimal%2C+the+discovery+of+intrinsically+disordered+proteins+may+contest+such+convention.+The+%E2%80%9Cfly-casting%E2%80%9D+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%2C+using+computational+means%2C+on+the+p53-MDM2+system%2C+performing+binding+simulations+of+MDM2+to+either+a+flexible+p53+peptide+or+its+exact+preorganized+analog.+We+employ+a+path+sampling+algorithm%2C+weighted+ensemble%2C+to+generate+large+ensembles+of+binding+pathways+and+to+calculate+rates+of+association.+Additionally%2C+the+effect+of+hydrodynamic+interactions%2C+often+omitted+in+implicit+solvent+simulations%2C+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%2C+indicating+the+importance+of+using+hydrodynamic+interactions+in+binding+simulations.&rft.date=2012-05-25&rft.type=University+of+Pittsburgh+ETD&rft.type=PeerReviewed&rft.format=application%2Fpdf&rft.language=en&rft.identifier=http%3A%2F%2Fd-scholarship-dev.library.pitt.edu%2F11867%2F1%2FWang_David_BPhil_ETD.pdf&rft.identifier=++Wang%2C+David+Wen+Rui++(2012)+Flexibility+vs.+preorganization%3A+molucular+simulations+of+MDM2-p53+peptide+binding+events.++Undergraduate+Thesis%2C+University+of+Pittsburgh.++++(Unpublished)++