title: The cis conformation of proline leads to weaker binding of a p53 peptide to MDM2 compared to trans.
abstract: The cis and trans conformations of the Xaa-Pro (Xaa: any amino acid) peptide bond are thermodynamically stable while other peptide bonds strongly prefer trans. The effect of proline cis-trans isomerization on protein binding has not been thoroughly investigated. In this study, computer simulations were used to calculate the absolute binding affinity for a p53 peptide (residues 17-29) to MDM2 for both cis and trans isomers of the p53 proline in position 27. Results show that the cis isomer of p53(17-29) binds more weakly to MDM2 than the trans isomer, and that this is primarily due to the difference in the free energy cost associated with the loss of conformational entropy of p53(17-29) when it binds to MDM2. The population of cis p53(17-29) was estimated to be 0.8% of the total population in the bound state. The stronger binding of trans p53(17-29) to MDM2 compared to cis may leave a minimal level of p53 available to respond to cellular stress. This study demonstrates that it is feasible to estimate the absolute binding affinity for an intrinsically disordered protein fragment binding to an ordered protein that are in good agreement with experimental results.
authors.affiliation: Institute for Bioinformatics and Evolutionary Studies, University of Idaho, Moscow, ID, United States.
authors.forename: Yingqian Ada
authors.initials: YA
authors.lastname: Zhan
authors.affiliation: Institute for Bioinformatics and Evolutionary Studies, University of Idaho, Moscow, ID, United States; Department of Physics, University of Idaho, Moscow, ID, United States. Electronic address: ytreberg@uidaho.edu.
authors.forename: F Marty
authors.initials: FM
authors.lastname: Ytreberg
mesh_terms: D011392:Proline / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry / Q000378:metabolism*; D013816:Thermodynamics; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53; D011392:Proline; D051736:Proto-Oncogene Proteins c-mdm2
keywords: Binding affinity; Intrinsically disordered protein; Molecular dynamics; Potential of mean force; cis–trans isomerization
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