Thermodynamics of phosphotyrosine peptide-peptoid hybrids binding to the p56Ick SH2 domain

A frequently used approach to transform peptides into more drug-like compounds is preparation of the corresponding peptoids or peptide-peptoid hybrids. Although peptoids have advantages, there may also be some disadvantages such as their increased flexibility and the reduced ability for hydrogen bond formation due to alkylation of the backbone amide nitrogen, which might affect the free Gibbs energy (AG). To obtain more insight into these contributions to AG, we performed thermodynamic analyses on the interaction between peptide-peptoid hybrids, based on the sequence -pTyr-Glu-Glu-Ile-, and the p56(Ick) (Lck) Src homology 2 domain. van't Hoff analysis was performed on binding data obtained from surface plasmon resonance competition experiments in a temperature range of 10-40 degrees C. It is observed that amino acid-peptoid substitutions do not have a systemic negative effect on the entropic contributions to AG. However, loss in hydrogen-bonding capacity of the backbone may strongly reduce the binding enthalpy and contribute to the observed lower binding affinity. Copyright (C) 2010 European Peptide Society and John Wiley & Sons, Ltd.