Conformational heterogeneity and dynamics are increasingly evoked in models of protein molecular recognition, but are challenging to experimentally characterize.  Combining the inherent temporal resolution of infrared (IR) spectroscopy with the spatial resolution afforded by selective incorporation of carbon deuterium (C-D) bonds, which provide frequency-resolved absorptions within a protein IR spectrum, enables characterization of local sites of proteins and their involvement in molecular recognition.  We have applied this approach to investigate the binding of the Src homology 3 (SH3) domain of the yeast protein Sho1 with its cognate proline-rich sequence of Pbs2.  The IR absorptions of C-D bonds introduced at residues along a peptide of the Pbs2 PR sequence report on the changes in the local environments upon binding to the SH3 domain, and interestingly, provide evidence for the population of multiple states in the complex with the SH3 domain.  An inability to resolve the states by NMR spectroscopy indicates that they are rapid interconverting.  The study suggests that the SH3 domain recognizes its cognate peptide with a component of induced fit molecular recognition involving the adoption of multiples states, which have previously gone undetected due to dynamics too fast to resolve using conventional methods.

Dynamic conformational heterogeneity in Src-homology 3 domain molecular recognition

252nd National Meeting (2016)

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