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Exploring the impact of polyproline II (P_II) conformational bias on the binding of peptides to the SEM-5 SH3 domain

¹ Department of Biochemistry and Molecular Biology, and Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, Galveston, Texas 77555, USA
² Redstorm Scientific, Inc., Galveston, Texas 77550, USA

(RECEIVED November 26, 2007; FINAL REVISION April 22, 2008; ACCEPTED April 23, 2008)

The left-handed polyproline II helical structure (P_II) is observed to be a dominant conformation in the disordered states of protein and small polypeptide chains, even when no prolines are present in the sequence. Recently, in work by Ferreon and Hilser, the energetics associated with Ala and Gly substitutions at a surface exposed proline site were determined calorimetrically by measuring the binding energetics of Sos peptide variants to the C-terminal Src Homology 3 domain of SEM-5. The results were interpreted as a significant conformational bias toward the bound conformation (i.e., P_II), even when the ligand is unbound. That study was not able to determine, however, whether the conformational bias of the peptides could be explained in terms other than that of a P_II preference. Here, we test, using a computer algorithm based on the hard sphere collision (HSC) model, the notion of whether a bias in the unbound states of the peptide ligands is specific for the P_II conformation, or if a bias to any other region of (, ) space can also result in the same observed binding energetics. The results of these computer simulations indicate that, of the regions of (, ) modeled for bias in the small peptides, only the bias to the P_II conformation, and at rates of bias similar to the experimentally observed rates, quantitatively reproduced the experimental binding energetics.

Keywords: protein structure/folding; forces and stability; ensembles; polyproline II; calorimetry

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