β-Hematin Crystal Formation: New Insights from Molecular Dynamics Simulations of Small Clusters in Condensed Phase

Understanding the driving forces observed during the first steps of β-hematin crystal formation is vital in view of developing new therapeutic treatments against malaria. In this context a new additive Amber force field specific to the cyclic dimer of ferriprotoporphyrin IX coordinated via Fe–O propionate bonds (FPD) was developed and validated in the context of a crystal model. The structure and dynamics of small clusters or oligomers of the FPD entity were studied by molecular dynamics in condensed phase. New hydrogen bond patterns were identified in the dynamical process of the simulations: the characteristic pair of coplanar hydrogen bonds reported in crystallographic structures between FPD sheets (Pagola et al. Nature 2000, 404, 307) is found to be in a subtle equilibrium with new hydrogen bonds between FPD located within the same sheet. Hydrophobic interactions appeared to play a key role in oligomer cohesion: clusters with intersheet hydrogen bonds are found unstable compared to clusters with embed...