Modeling and dynamical analysis of the full-length structure of factor XII with zinc.

Zinc (II), the second most abundant transition metal in blood, binds to the initiator of the contact pathway, factor XII (FXII). This binding induces conformational changes in the structure of FXII eventually leading to its activation. Despite many in vitro and in vivo studies on zinc-mediated activation of FXII, its molecular mechanism remains elusive mainly due to absence of a full-length structural model of FXII. To this end, this study investigated the role of zinc in the structure and dynamics of the full-length structure FXII that was obtained through molecular modeling. We have used four structural templates covering more than 70% of the FXII sequence and the remaining interconnecting regions were built by loop modeling. The resulting full-length structure of FXII contained disordered regions, but in comparison to the AlphaFold (AF) prediction, our full-length model represented a more realistic structure because of the disordered regions which were modeled to yield a more compact full-length structure in our model than the AF structure. Other than the disordered regions, our model and AF prediction were highly similar. The resulting full-length FXII structure was used to generate different systems representing the zinc-bound form (holo). Further to assess the contribution of the disulfide bridges, we also analyzed the apo and holo FXII structures with oxidized or reduced cysteine side-chains. Simulations suggested zinc binding conferred rigidity to the structure, particularly to the light chain of FXII. Zinc binding alone was sufficient to limit the backbone flexibility while 15 disulfide bonds, which were scattered throughout the structure, made a less significant contribution to the backbone rigidity. Altogether our results provide insights into the first realistic full-length structure of FXII focusing on the impact of structural zinc and disulfide bridges in the dynamics of this structure.