Direct observations of conformational distributions of intrinsically disordered p53 peptides using UV Raman and explicit solvent simulations

Xiong, K and Zwier, MC and Myshakina, NS and Burger, VM and Asher, SA and Chong, LT (2011) Direct observations of conformational distributions of intrinsically disordered p53 peptides using UV Raman and explicit solvent simulations. Journal of Physical Chemistry A, 115 (34). 9520 - 9527. ISSN 1089-5639

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Abstract

We report the first experimental measurements of Ramachandran Ψ-angle distributions for intrinsically disordered peptides: the N-terminal peptide fragment of tumor suppressor p53 and its P27S mutant form. To provide atomically detailed views of the conformational distributions, we performed classical, explicit-solvent molecular dynamics simulations on the microsecond time scale. Upon binding its partner protein, MDM2, wild-type p53 peptide adopts an α-helical conformation. Mutation of Pro27 to serine results in the highest affinity yet observed for MDM2-binding of the p53 peptide. Both UV resonance Raman spectroscopy (UVRR) and simulations reveal that the P27S mutation decreases the extent of PPII helical content and increases the probability for conformations that are similar to the α-helical MDM2-bound conformation. In addition, UVRR measurements were performed on peptides that were isotopically labeled at the Leu26 residue preceding the Pro27 in order to determine the conformational distributions of Leu26 in the wild-type and mutant peptides. The UVRR and simulation results are in quantitative agreement in terms of the change in the population of non-PPII conformations involving Leu26 upon mutation of Pro27 to serine. Finally, our simulations reveal that the MDM2-bound conformation of the peptide is significantly populated in both the wild-type and mutant isolated peptide ensembles in their unbound states, suggesting that MDM2 binding of the p53 peptides may involve conformational selection. © 2011 American Chemical Society.

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Details

Item Type:	Article
Status:	Published
Creators/Authors:	Creators Email Pitt Username ORCID Xiong, K Zwier, MC Myshakina, NS Burger, VM Asher, SA asher@pitt.edu ASHER Chong, LT
Date:	1 September 2011
Date Type:	Publication
Journal or Publication Title:	Journal of Physical Chemistry A
Volume:	115
Number:	34
Page Range:	9520 - 9527
DOI or Unique Handle:	10.1021/jp112235d
Schools and Programs:	Dietrich School of Arts and Sciences > Chemistry
Refereed:	Yes
ISSN:	1089-5639
MeSH Headings:	Binding Sites; Chemistry, Physical; Computer Simulation; Humans; Leucine--chemistry; Leucine--metabolism; Models, Molecular; Peptide Fragments--chemistry; Peptide Fragments--genetics; Peptide Fragments--metabolism; Proline--chemistry; Proline--metabolism; Protein Binding; Protein Structure, Secondary; Protein Structure, Tertiary; Proto-Oncogene Proteins c-mdm2--chemistry; Proto-Oncogene Proteins c-mdm2--genetics; Proto-Oncogene Proteins c-mdm2--metabolism; Serine--chemistry; Serine--metabolism; Solvents--chemistry; Spectrum Analysis, Raman; Tumor Suppressor Protein p53--chemistry; Tumor Suppressor Protein p53--genetics; Tumor Suppressor Protein p53--metabolism
Other ID:	NLM NIHMS293208, NLM PMC3161171
PubMed Central ID:	PMC3161171
PubMed ID:	21528875
Date Deposited:	13 Feb 2013 16:16
Last Modified:	02 Feb 2019 15:57
URI:	http://d-scholarship-dev.library.pitt.edu/id/eprint/17284

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