Computational studies and peptidomimetic design for the human p53–MDM2 complex
dc.contributor.author | Zhong, Haizhen | en_US |
dc.contributor.author | Carlson, Heather A. | en_US |
dc.date.accessioned | 2006-04-19T14:02:15Z | |
dc.date.available | 2006-04-19T14:02:15Z | |
dc.date.issued | 2005-01-01 | en_US |
dc.identifier.citation | Zhong, Haizhen; Carlson, Heather A. (2005)."Computational studies and peptidomimetic design for the human p53–MDM2 complex." Proteins: Structure, Function, and Bioinformatics 58(1): 222-234. <http://hdl.handle.net/2027.42/34979> | en_US |
dc.identifier.issn | 0887-3585 | en_US |
dc.identifier.issn | 1097-0134 | en_US |
dc.identifier.uri | https://hdl.handle.net/2027.42/34979 | |
dc.identifier.uri | http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=retrieve&db=pubmed&list_uids=15505803&dopt=citation | en_US |
dc.description.abstract | The interaction between human p53 and MDM2 is a key event in controlling cell growth. Many studies have suggested that a p53 mimic would be sufficient to inhibit MDM2 to reduce cell growth in cancerous tissue. In order to design a potent p53 mimic, molecular dynamics (MD) simulations were used to examine the binding interface and the effect of mutating key residues in the human p53–MDM2 complex. The Generalized Born surface area (GBSA) method was used to estimate free energies of binding, and a computational alanine-scanning approach was used to calculate the relative effects in the free energy of binding for key mutations. Our calculations determine the free energy of binding for a model p53–MDM2 complex to be −7.4 kcal/mol, which is in very good agreement with the experimentally determined values (−6.6–−8.8 kcal/mol). The alanine-scanning results are in good agreement with experimental data and calculations by other groups. We have used the information from our studies of human p53–MDM2 to design a Β-peptide mimic of p53. MD simulations of the mimic bound to MDM2 estimate a free energy of binding of −8.8 kcal/mol. We have also applied alanine scanning to the mimic–MDM2 complex and reveal which mutations are most likely to alter the binding affinity, possibly giving rise to escape mutants. The mimic was compared to nutlins, a new class of inhibitors that block the formation of the p53–MDM2 complex. There are interesting similarities between the nutlins and our mimic, and the differences point to ways that both inhibitors may be improved. Finally, an additional hydrophobic pocket is noted in the interior of MDM2. It may be possible to design new inhibitors to take advantage of that pocket. Proteins 2005. © 2004 Wiley-Liss, Inc. | en_US |
dc.format.extent | 438933 bytes | |
dc.format.extent | 3118 bytes | |
dc.format.mimetype | application/pdf | |
dc.format.mimetype | text/plain | |
dc.language.iso | en_US | |
dc.publisher | Wiley Subscription Services, Inc., A Wiley Company | en_US |
dc.subject.other | Chemistry | en_US |
dc.subject.other | Biochemistry and Biotechnology | en_US |
dc.title | Computational studies and peptidomimetic design for the human p53–MDM2 complex | en_US |
dc.type | Article | en_US |
dc.rights.robots | IndexNoFollow | en_US |
dc.subject.hlbtoplevel | Health Sciences | en_US |
dc.description.peerreviewed | Peer Reviewed | en_US |
dc.contributor.affiliationum | Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan | en_US |
dc.contributor.affiliationum | Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan ; Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, 428 Church St., Ann Arbor, MI 48109-1065 | en_US |
dc.identifier.pmid | 15505803 | en_US |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/34979/1/20275_ftp.pdf | en_US |
dc.identifier.doi | http://dx.doi.org/10.1002/prot.20275 | en_US |
dc.identifier.source | Proteins: Structure, Function, and Bioinformatics | en_US |
dc.owningcollname | Interdisciplinary and Peer-Reviewed |
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