The leucine zipper interaction between MAX and c-MYC has been studied using mass spectrometry and drift time ion mobility Mass spectrometry (DT IM-MS) in addition to circular dichroism spectroscopy. Peptides comprising the leucine zipper sequence with.(c-MYC-Zip residues 402-434) And without a postulated small-molecule binding region (cMYC-Zip residues 402-434) have been synthesized along with the corresponding MAX leucine zipper (MAX-Zip residues 74-102). c-MYC-Zip:MAX-Zip Complexes are observed both in the absence and in the presence of the reported small-molecule inhibitor 10058-F4 for both forms of c-MYC-Zip. DT IM-MS in combination with molecular dynamics (MD), shows that the c-MYC-Zip:MAX-Zip complex [M + 5H](5+) exists in two conformations, one extended with a collision cross section (CCS) of 1164 +/- 9.3 angstrom(1) and one compact with a CCS of 982 +/- 6.6 angstrom(2); similar value's are observed for the two forms of-c-MYC-Zip Delta DT:MAX-Zip: Candidate geonietries for the complexes have been evaluated with MD simulations The helical leucine zipper structure previously determined from NMR Measurements (Lavigne, P; et al. J. Mol. Biol. 1998, 281, 165), altered to -include ' the DT region and subjected to a gas phase minimization, yields a CCS of 1247 angstrom(2), which agrees with the extended conformation we observe experimentally. More extensive MD simulations provide compact complexes which are found to be highlrdisOrdered, with CCSs that correspond to the compact form from experiment. In the presence of the ligand, the leucine zipper conformation is completely inhibited andonly,the,more disordered species is observed, providing a novel method to study the effect of interactions Of disordered systems and subsequent: inhibition,olthe.formation of an ordered helical complex.