Stretching the immunoglobulin 27 domain of the titin protein: the dynamic energy landscape.

Molecular simulations are carried out on the Immunoglobulin 27 domain of the titin protein. The energy landscape is mapped out using an implicit solvent model, and molecular dynamics simulations are run with the solvent explicitly modeled. Stretching a protein is shown to produce a dynamic energy landscape in which the energy minima move in configuration space, change in depth, and are created and destroyed. The connections of these landscape changes to the mechanical unfolding of the Immunoglobulin 27 domain are addressed. Hydrogen bonds break upon stretching by either intrabasin processes associated with the movement of energy minima, or interbasin processes associated with transitions between energy minima. Intrabasin changes are reversible and dominate for flexible interactions, whereas interbasin changes are irreversible and dominate for stiff interactions. The most flexible interactions are Glu-Lys salt bridges, which can act like tethers to bind strands even after all backbone interactions between the strands have been broken. As the protein is stretched, different types of structures become the lowest energy structures, including structures that incorporate nonnative hydrogen bonds. Structures that have flat energy versus elongation profiles become the lowest energy structures at elongations of several Angstroms, and are associated with the unfolding intermediate state observed experimentally.