Detection of native-state nonadditivity in double mutant cycles via hydrogen exchange

Journal of the American Chemical Society
Joshua A BoyerAndrew L Lee

Abstract

Proteins have evolved to exploit long-range structural and dynamic effects as a means of regulating function. Understanding communication between sites in proteins is therefore vital to our comprehension of such phenomena as allostery, catalysis, and ligand binding/ejection. Double mutant cycle analysis has long been used to determine the existence of communication between pairs of sites, proximal or distal, in proteins. Typically, nonadditivity (or "thermodynamic coupling") is measured from global transitions in concert with a single probe. Here, we have applied the atomic resolution of NMR in tandem with native-state hydrogen exchange (HX) to probe the structure/energy landscape for information transduction between a large number of distal sites in a protein. Considering the event of amide proton exchange as an energetically quantifiable structural perturbation, m n-dimensional cycles can be constructed from mutation of n-1 residues, where m is the number of residues for which HX data is available. Thus, efficient mapping of a large number of couplings is made possible. We have applied this technique to one additive and two nonadditive double mutant cycles in a model system, eglin c. We find heterogeneity of HX-monitored coup...Continue Reading

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