Please use this identifier to cite or link to this item: https://doi.org/10.1038/s41598-017-15930-4
Title: Characterizing the conformational landscape of MDM2-binding p53 peptides using Molecular Dynamics simulations
Authors: Yadahalli, S
Li, J 
Lane, D.P 
Gosavi, S
Verma, C.S 
Keywords: MDM2 protein, human
peptide
protein binding
protein MDM2
protein p53
TP53 protein, human
binding site
chemistry
genetics
human
molecular dynamics
mutation
protein conformation
protein secondary structure
thermodynamics
X ray crystallography
Binding Sites
Crystallography, X-Ray
Humans
Molecular Dynamics Simulation
Mutation
Peptides
Protein Binding
Protein Conformation
Protein Structure, Secondary
Proto-Oncogene Proteins c-mdm2
Thermodynamics
Tumor Suppressor Protein p53
Issue Date: 2017
Publisher: Nature Publishing Group
Citation: Yadahalli, S, Li, J, Lane, D.P, Gosavi, S, Verma, C.S (2017). Characterizing the conformational landscape of MDM2-binding p53 peptides using Molecular Dynamics simulations. Scientific Reports 7 (1) : 15600. ScholarBank@NUS Repository. https://doi.org/10.1038/s41598-017-15930-4
Abstract: The conformational landscapes of p53 peptide variants and phage derived peptide (12/1) variants, all known to bind to MDM2, are studied using hamiltonian replica exchange molecular dynamics simulations. Complementing earlier observations, the current study suggests that the p53 peptides largely follow the 'conformational selection' paradigm in their recognition of and complexation by MDM2 while the 12/1 peptides likely undergo some element of conformational selection but are mostly driven by 'binding induced folding'. This hypothesis is further supported by pulling simulations that pull the peptides away from their bound states with MDM2. This data extends the earlier mechanisms proposed to rationalize the entropically driven binding of the p53 set and the enthalpically driven binding of the 12/1 set. Using our hypothesis, we suggest mutations to the 12/1 peptide that increase its helicity in simulations and may, in turn, shift the binding towards conformational selection. In summary, understanding the conformational landscapes of the MDM2-binding peptides may suggest new peptide designs with bespoke binding mechanisms. © 2017 The Author(s).
Source Title: Scientific Reports
URI: https://scholarbank.nus.edu.sg/handle/10635/174385
ISSN: 2045-2322
DOI: 10.1038/s41598-017-15930-4
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