Thesis (M.S., Bioinformatics & Computational Biology) -- University of Idaho, 2016 | Peptide bonds in proteins strongly prefer trans conformation. And the cis conformation is more frequently associated with prolines in intrinsically disordered proteins (IDPs) than structured proteins. It is not currently well understood how the cis-trans isomerization of proline modifies protein-protein binding in IDPs.
In this thesis, computer simulations were used to study how the cis and trans conformations of a proline in the IDP p53 modify its affinity for MDM2. 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.
In addition, a survey was conducted analyzing the frequencies of both cis and trans conformations in a database contaning membrane protein molecular recognition features (mpMoRFs). These mpMoRFs are a class of IDPs in membrane that become structured when they bind to their partners. Analysis of amino acid composition showed that mpMoRFs consist both order- and disorder-promoting amino acids. The peptide bonds for Xaa-Pro mpMoRFs are distinct from natively structured proteins. In mpMoRFs, only 0.11%/0.75% of peptide bonds are in cis for non-proline/proline, in contrast to natively structured proteins where 0.03%/5.2% are in cis for non-proline/proline. These results suggest that cis-trans isomerization in mpMoRFs are special. More researches are required to fully understand their functions.