The central domain of smooth muscle caldesmon contains a highly charged region consisting of ten 13-residue repeats. Experimental evidence obtained from the intact protein and fragments thereof suggests that this entire region forms a single stretch of stable α-helix. We have carried out molecular dynamics simulations on peptides consisting of one, two and three repeats to examine the mechanism of α-helical stability of the central domain at the atomic level. All three peptides show high helical stability on the timescale of the MD simulations. Deviations from α-helical structure in all the simulations arise mainly from the formation of long stretches of π-helix. Interconversion between α-helical and π-helical conformations occurs through insertion of water molecules into α-helical hydrogen bonds and subsequent formation of reverse turns. The α-helical structure is stabilized by electrostatic interactions (salt bridges) between oppositely charged sidechains with i,i+4 spacings, while the π-helix is stabilized by i,i+5 salt bridge interactions. Possible i,i+3 salt bridges are of minor importance. There is a strong preference for salt bridges with a Glu residue N-terminal to a basic sidechain as compared to the opposite orientation. In the double and triple repeat peptides, strong i,i+4 salt bridges exist between the last Glu residue of one repeat and the first Lys residue of the next. This demonstrates a relationship between the repetitive nature of the central domain sequence and its ability to form very long stretches of α-helical structure.

Key words: α-helix stabilization, Salt bridges, π-helix.