Our goal is to predict the alpha-helix contents of natural-sequence peptides. The rules for prediction are being developed and tested now. The zero-order rules are based on the three parameters of standard helix-coil transition theory (sigma,s,delta H). Recent work has shown that there are large differences between the intrinsic helix-forming tendencies (the s values) of different amino acids when these are determined by substitution in alanine-based reference peptides. The first-order rules include additional terms for side-chain interactions, such as ion pair interactions, which we have been determining recently. Delta H, the enthalpy change of helix formation per residue, is being determined calorimetrically in collaboration with Prof. D.W. Bolen. The other parameters are being determined from thermal unfolding, curves measured by circular dichroism for peptides with repeating sequences and varying chain lengths. The fitting is being done in collaboration with Prof. J.A. Schellman. As background for this work, the position dependence of a substitution is being studied in comparison with the effect predicted by the Lifson-Roig theory and the context dependence is studied by varying neighboring residues. The difference between the s values found in alanine-based peptides and in host-guest Copolymers with hydroxybutyl-L-glutamine (HBLG) as the host is thought to arise from a strong context dependence of the results when HBLG is the host. We will test this hypothesis by experiments on context dependence.
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