  Leucine zippers are alpha helical monomers dimerized to a coiled coil
structure. Various scenarios for dimerization span interaction of unstructured
monomers that form alpha helices in the process of dimerization to preformed
alpha helical monomers dimerizing.Another suggested possibility, a trigger
sequence hypothesis (M. O. Steinmetz et al., Proc. Natl. Acad. Sci. U. S. A.
2007, 104, 7062-7067), is that a C terminal (CT) part of each monomer is a
trigger sequence that is dimerized and, subsequently, the remainder N terminal
(NT) part of each monomer (that is partially ordered) zips together to form the
coiled coil. In this work, methods are developed to computationally explore the
trigger sequence hypothesis based on an extension of a previously introduced
(R. I. Cukier, J. Chem. Phys. 2011, 134, 045104) Hamiltonian Temperature
Replica Exchange Method Mean Square (HTREM_MS) procedure, which scales the
Hamiltonian in both potential and kinetic energies, to enhance sampling
generically, along with additional restraints to enhance sampling in desired
regions of conformational space. The method is applied to a 31-residue
truncation of the 33-residue leucine zipper (GCN4-p1) of the yeast
transcriptional activator GCN4. Using a variety of HTREM_MS simulations, we
find that the NT of one monomer of the dimer becomes disordered when the NT
parts of the monomers are separated. In contrast, when the CT parts of the
monomers are separated, both monomers remain alpha helical. These simulations
suggest that the CT does act as a trigger sequence and are consistent with a
disordered NT. We also investigate whether the disordered NT can be induced to
re-form the dimerized leucine zipper. It does, but with some lack of recovery
of alpha helical hydrogen bonding structure in the NT.
