Please use this identifier to cite or link to this item:
|Title:||Systematic mutational analysis of an ubiquitin ligase (MDM2)-binding peptide: Computational studies|
|Source:||Liu, Y., Lane, D.P., Verma, C.S. (2011-12). Systematic mutational analysis of an ubiquitin ligase (MDM2)-binding peptide: Computational studies. Theoretical Chemistry Accounts 130 (4-6) : 1145-1154. ScholarBank@NUS Repository. https://doi.org/10.1007/s00214-011-1049-y|
|Abstract:||To understand the importance of amino acids that comprise the peptide PMI (p53-MDM2/MDMX inhibitor), a p53-mimicking peptide with high affinity for the ubiquitin ligase MDM2, computational alanine scanning has been carried out using various protocols. This approach is very useful for identifying regions of a peptide that can be mutated to yield peptides that bind to their targets with higher affinities. Computational alanine scanning is a very useful technique that involves mutating each amino acid of the peptide in its complex with its target (MDM2 in the current study) to alanine, running short simulations on the mutated complex and computing the difference in interaction energies between the mutant peptides and the target protein (MDM2 in the current study) relative to the interaction energy of the original (wild-type) peptide and the target protein (MDM2 in the current study). We find that running multiple short simulations yield values of computed binding affinities (enthalpies) that are similar to those obtained from a long simulation and are well correlated with the trends in the data available from experiments that used Surface Plasmon Resonance to obtain dissociation constants. The p53-mimicking peptides contain three amino acids (F19, W23 and L26) that are major determinants of the interactions between the peptides and MDM2 and form an essential motif. We find in the current study that the trends amongst the contributions to experimental binding affinities of the hydrophobic residues F19, W23 and L26 are the best reproduced in all the computational protocols examined here. This study suggests that running such short simulations may provide a rapid method to redesign peptides to obtain high-affinity variants against a target protein. We further observe that modelling an extended conformation at the C-terminus of the helical PMI peptides, in accord with the conformation of the p53-peptide complexed to MDM2, reproduces the trends seen amongst the experimental affinities of the peptides that carry the alanine mutations at their C-termini. This suggests that some of the mutant peptides possibly interconvert between helical and extended states and can bind to MDM2 in either conformation. This novel feature, not obvious from the crystallographic data, if factored into modelling protocols, may yield novel high-affinity peptides. Our findings suggest that such protocols may enable rapid investigations of at least certain types of amino acid mutations, notably from large to small amino acids. © 2011 Springer-Verlag.|
|Source Title:||Theoretical Chemistry Accounts|
|Appears in Collections:||Staff Publications|
Show full item record
Files in This Item:
There are no files associated with this item.
checked on Mar 19, 2018
WEB OF SCIENCETM
checked on Mar 19, 2018
checked on Mar 11, 2018
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.