Side-Chain Interactions Form Late and Cooperatively in the Binding Reaction between Disordered Peptides and PDZ Domains

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• 作者：S. Raza Haq ; Celestine N. Chi ; Anders Bach ; Jakob Dogan ; 脜ke Engstr枚m ; Greta Hultqvist ; O. Andreas Karlsson ; Patrik Lundstr枚m ; Linda C. Montemiglio ; Kristian Str酶mgaard ; Stefano Gianni ; Per Jemth
• 刊名：The Journal of the American Chemical Society
• 出版年：2012
• 出版时间：January 11, 2012
• 年：2012
• 卷：134
• 期：1
• 页码：599-605
• 全文大小：386K
• 年卷期：v.134,no.1(January 11, 2012)
• ISSN：1520-5126

文摘

Intrinsically disordered proteins are very common and mediate numerous protein鈥損rotein and protein鈥揇NA interactions. While it is clear that these interactions are instrumental for the life of the mammalian cell, there is a paucity of data regarding their molecular binding mechanisms. Here we have used short peptides as a model system for intrinsically disordered proteins. Linear free energy relationships based on rate and equilibrium constants for the binding of these peptides to ordered target proteins, PDZ domains, demonstrate that native side-chain interactions form mainly after the rate-limiting barrier for binding and in a cooperative fashion. This finding suggests that these disordered peptides first form a weak encounter complex with non-native interactions. The data do not support the recent notion that the affinities of intrinsically disordered proteins toward their targets are generally governed by their association rate constants. Instead, we observed the opposite for peptide鈥揚DZ interactions, namely, that changes in K_d correlate with changes in k_off.