?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%2F19518%2F&rft.title=Efficient+Computer+Simulations+of+Protein-Peptide+Binding+Using+Weighted+Ensemble+Sampling&rft.creator=Zwier%2C+Matthew+C&rft.description=Molecular+dynamics+simulations+can%2C+in+principle%2C+provide+detailed+views+of+protein-protein+association+processes.+However%2C+these+processes+frequently+occur+on+timescales+inaccessible+on+current+computing+resources.+These+are+not+particularly+slow+processes%2C+but+rather+they+are+rare+%E2%80%94+fast+but+infrequent.+The+weighted+ensemble+(WE)+sampling+approach+provides+a+way+to+exploit+this+separation+of+timescales+and+focus+computing+power+efficiently+on+rare+events.+In+this+work%2C+it+is+demonstrated+that+WE+sampling+can+be+used+to+efficiently+obtain+kinetic+rate+constants%2C+pathways%2C+and+energy+landscapes+of+molecular+association+processes.+Chapter+1+of+this+dissertation+further+discusses+the+need+for+enhanced+sampling+techniques+like+the+WE+approach.+In+Chapter+2%2C+WE+sampling+is+used+to+study+the+kinetics+of+association+of+four+model+molecular+recognition+systems+(methane%2Fmethane%2C+Na%2B%2FCl%E2%80%93%2C+methane%2Fbenzene%2C+and+K%2B%2F18-crown-6+ether)+using+molecular+dynamics+(MD)+simulations+in+explicit+water.+WE+sampling+reproduces+straightforward+%E2%80%9Cbrute+force%E2%80%9D+results+while+increasing+the+efficiency+of+sampling+by+up+to+three+orders+of+magnitude.+Importantly%2C+the+efficiency+of+WE+simulation+increases+with+increasing+complexity+of+the+systems+under+consideration.+In+Chapter+3%2C+weighted+ensemble+Brownian+dynamics+(BD)+simulations+are+used+to+explore+the+association+between+a+13-residue+fragment+of+the+p53+tumor+suppressor+and+the+MDM2+oncoprotein.+The+association+rates+obtained+compare+favorably+with+experiment.+By+directly+comparing+both+flexible+and+pre-organized+variants+of+p53%2C+it+is+shown+that+the+%E2%80%9Cfly-casting%E2%80%9D+effect%2C+by+which+natively+unstructured+proteins+may+increase+their+association+rates%2C+is+not+significant+in+MDM2-p53+peptide+binding.+Including+hydrodynamic+interactions+in+the+simulation+model+dramatically+alters+the+association+rate%2C+indicating+that+the+detailed+motion+of+solvent+may+have+substantial+effects+on+the+kinetics+of+protein-protein+association.+In+Chapter+4%2C+an+all-atom+molecular+dynamics+simulation+of+p53-MDM2+binding+is+described.+We+obtain+an+association+rate+that+agrees+with+the+experimental+value.+The+free+energy+landscape+of+binding+is+%E2%80%9Cfunnel-like%E2%80%9D%2C+downhill+after+the+initial+encounter+between+p53+and+MDM2.+Together%2C+the+studies+described+here+establish+that+WE+sampling+is+highly+effective+in+simulating+rare+molecular+association+events.&rft.date=2013-09-30&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%2F19518%2F1%2Fmcz_dissertation.pdf&rft.identifier=++Zwier%2C+Matthew+C++(2013)+Efficient+Computer+Simulations+of+Protein-Peptide+Binding+Using+Weighted+Ensemble+Sampling.++Doctoral+Dissertation%2C+University+of+Pittsburgh.++++(Unpublished)++