Length dependence of the coil <--> beta-sheet transition in a membrane environment

The most abundant structural element in protein aggregates is the beta-sheet. Designed peptides that fold into a beta-sheet structure upon binding to lipid membranes are useful models to elucidate the thermodynamic characteristics of the random coil <-->beta-structure transition. Here, we examine the effect of strand length on the random coil <--> beta-sheet transition of the (KIGAKI)n peptide with the total chain length varying between 7 and 30 amino acids. The beta-sheet content of the peptides in the presence and absence of membranes was measured with circular dichroism spectroscopy. The peptides were titrated with small unilamellar lipid vesicles, and the thermodynamic binding parameters were determined with isothermal titration calorimetry (ITC). Membrane binding includes at least two processes, namely (i) the transfer of the peptide from the aqueous phase to the lipid surface and (ii) the conformational change from a random coil conformation to a beta-sheet structure. CD spectroscopy and ITC analysis demonstrate that beta-sheet formation depends cooperatively on the peptide chain length with a distinct increase in beta-structure for n > 10-12. Binding to the lipid membrane is an entropy-driven process as the binding enthalpy is always endothermic. The contribution of the beta-sheet folding reaction to the overall process was determined with analogues of the KIGAKI repeat where two adjacent amino acids were replaced by their D-enantiomers. The folding reaction for peptides with n >or= 12 is characterized by a negative free folding energy of DeltaG(degree)beta approximately equal -0.15 kcal/mol per amino acid residue. The folding step proper is exothermic with DeltaH(degree)(beta) approximately equal -0.2 to -0.6 kcal/mol per residue and counteracted by a negative entropy term TDeltaS(degree)(beta) = -0.1 to -0.5 kcal/mol per residue, depending on the chain length (18