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.

journal_name

Arch Biochem Biophys

authors

Zhan YA,Ytreberg FM

doi

10.1016/j.abb.2015.03.021

subject

Has Abstract

pub_date

2015-06-01 00:00:00

pages

22-9

eissn

0003-9861

issn

1096-0384

pii

S0003-9861(15)00157-5

journal_volume

575

pub_type

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