Molecular dynamics study of alpha-helical coiled-coils: Hydrophobic interactions and their impact on helix orientation and coiled-coil stability

The two-stranded α-helical coiled-coil found in the enzyme seryl t-RNA synthetase (STS) folds as an antiparallel coiled-coil, the typical orientation for coiled-coils in globular proteins. On the other hand coiled-coils found in DNA-binding proteins like GCN4 typically maintain a parallel orientation. This study addresses the following questions: what role do hydrophobic interactions play in influencing the orientation of helices in a coiled-coil and what impact do they have on coiled-coil stability?; The molecular dynamics program CHARMm was used to build parallel and antiparallel models of the STS and GCN4 coiled-coils in vacuo and to evaluate the influence of hydrophobic interactions. Native models of the STS antiparallel coiled-coil and the GCN4 parallel coiled-coil, based on the x-ray crystallographic structures, were compared to designed models of a STS parallel and a GCN4 antiparallel coiled-coil. Differences in hydrophobic packing and residue accessibility in each orientation were evaluated using the Lee and Richards method. Also, solvation free energies calculated using the Eisenberg and McLachlan method were used to predict the relative stability of each orientation in terms of hydrophobic interactions.; The results showed the antiparallel orientation was the preferred orientation for a two-stranded α-helical coiled-coil in terms of hydrophobic packing and residue accessibility. Furthermore solvation free energy calculations showed the antiparallel orientation was more stable in terms of hydrophobic interactions than its parallel counterpart. Thus, these results suggest that while hydrophobic interactions in isolation dictate an antiparallel orientation, there are other overriding factors such as electrostatics that ultimately determine the parallel orientation of coiled-coils found in DNA-binding proteins.