Decoding the Host-Parasite Protein Interactions Involved in Cerebral Malaria Through Glares of Molecular Dynamics Simulations

Malaria causes millions of deaths every year. The malaria parasite spends a substantial part of its life cycle inside human erythrocytes. Inside erythrocytes, it synthesizes and displays various proteins onto the erythrocyte surface, such as Plasmodium falciparum erythrocytic membrane protein-1 (PfEMP1). This protein contains cysteine-rich interdomain region (CIDR) domains which have many subtypes based on sequence diversity and can cross-talk with host molecules. The CIDR alpha 1.4 subtype can attach host endothelial protein C receptor (EPCR). This interaction facilitates infected erythrocyte adherence to brain endothelium and subsequent development of cerebral malaria. Through molecular dynamics simulations in conjunction with the molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) method, we explored the mechanism of interaction in the CIDR alpha 1-EPCR complex We examined the structural behavior of two CIDR alpha 1 molecules (encoded by HB3-isolate var03-gene and IT4-isolate var07-gene) with EPCR unbound and bound (complex) forms. (CIDR)-C-HB3var03 alpha 1 in apo and complexed with EPCR was comparatively more stable than( IT4var07)CIDR alpha 1. Both of the complexes adopted two distinct conformational energy states. The hydrophobic residues played a crucial role in the binding of both complexes. For (CIDR)-C-HB3var03 alpha 1-EPCR, the dominant energetic components were total polar interactions, while in (CIDR)-C- IT4var07 alpha 1-EPCR, the primary interaction was van der Waals and nonpolar solvation energy. The study also revealed details such as correlated conformational motions and secondary structure evolution. Further, it elucidated various hotspot residues involved in protein-protein recognition. Overall, our study provides additional information on the structural behavior of CIDR molecules in unbound and receptor-bound states, which will help to design potent inhibitors.