Developing new drugs which would inhibit haemozoin formation is an established therapeutic strategy against <i>Plasmodium</i><i> falciparum</i> and Malaria. In this context, we have developed a refined Amber type force field (FF) for the μ-propionato dimer of ferriprotoporphyrin IX (FPD) based on the crystal structure of synthetic haemozoin or β-hematin. This work involved elementary building blocks, and was carried out by using the PyRED program at RED Server Development, http://q4md-forcefieldtools.org/REDServer-Development/. PyRED allows atomic charge derivation for molecular fragments as well as atom typing, FF library building, and FF parameter generation. This new FF represents an update of the work we published in the Crystal Growth & Design journal in 2016. It involved a new charge model, as well as revised bond, angle and dihedral parameters. New atomic charges were derived to refine the description of π-π and π-cation interactions. The bond and angle parameters were determined by linear interpolation. Key dihedral angle parameters were determined to accurately reproduce quantum mechanics potentials. FF validation was carried out based on a crystal model of β-hematin, as well as FPD oligomers using molecular dynamics simulations (MD) in condensed phase. MD results were compared to those published in our previous work. The suitability of the model to reproduce the interactions of porphyrins and of FPD through π-π stacking is assessed. Preliminary results obtained with this improved FF demonstrate excellent agreements with experimental data. Results obtained with this new FF clearly show a lower statistical weight for FPD structures with intra-FPD hydrogen bonds (HB). The molecular building block approach allows the introduction of alkyl groups in place of the propionic acid moieties in FPD. Hence the involvement of HB in the anchoring process of FPD in the β-hematin crystal as well as π-π interactions were studied by MD.

Development of a refined force field for β-hematin and molecular dynamics study

254th National Meeting (2017)

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