THE DESIGN OF EFFICIENT ALPHA-HELICAL C-CAPPING AUXILIARIES

We have designed a series of C-capping auxiliaries with various chain lengths based on alkyldiamines and monoguanylated diamines. These capp ing groups were incorporated synthetically at the C-terminus of a deri vative of a poly-Ala helix. The free energy of interaction of the capp ing moiety (Delta Delta G(c) degrees) with the C-terminus of the helix was assessed by circular dichroism and calculated using a modified Li fson-Roig formalism described by Doig and Baldwin (Doig, A. J.; Baldwi n, R. L. Protein Sci. 1995, 4, 1325) as well as AGADIR2s, an algorithm based on helix-coil transition theory developed by Munoz and Serrano (Munoz, V.; Serrano, L. Biopolymers 1997, 41, 495-509). The alkyldiami ne auxiliaries serve as modest helix stabilizers with Delta Delta G(c) degrees, = -0.2 to -0.5 kcal mol(-1). The incorporation of monoguanyl ated diamines at the C-terminus leads to a further increase in cr-heli city resulting in Delta Delta G(c) degrees = -0.3 to -0.7 kcal mol(-1) . Furthermore, a D-Arg carboxamide auxiliary is demonstrated to be an efficient C-capping residue with Delta Delta G(c) degrees = -1.2 kcal mol(-1). At high concentrations of NaCl (2 M), the capping effect is o nly partially screened, suggesting that this auxiliary imparts stabili zation via charge/dipole interactions as well as through the formation of specific H-bonds between the auxiliary and C-terminal main chain c arbonyls.