Distinguishing Features of Aquaglyceroporin in Plasmodium Falciparum: Comparative Molecular Dynamics Simulations of Three Aquaporins

Abstract

Aquaporins help to maintain water homeostasis and diverse members have been identified across all three kingdoms of life (http://bioinfo.iitk.ac.in/MIPModDB). These remarkable channel proteins facilitate the transport of water and other neutral solutes across biomembranes. Their selectivity has been attributed to two constrictions within the channel namely aromatic/arginine selectivity filter (SF) and the conserved NPA motif. Despite the wealth of data available from experimental and computational studies, the physical basis of selectivity is still not completely understood. A recent structure of an aquaporin (PfAQP) from the malarial parasite Plasmodium facliparum, which is also a potential drug target for malaria,was found to possess SF identical to a glycerol-specific aquaglyceroporin (GlpF). Interestingly, it was observed that PfAQP transports both water and glycerol equally efficiently.The molecular basis of dual specificity in PfAQP continues to puzzle researchers. Although the overall fold is same, one of the distinguishing features could be distinct non-covalent interactions specific to only PfAQP. In order to find out any such interaction, we have carried out MD simulations of PfAQP and compared with water-selective AQP1 and glycerol-specific GlpF in explicit lipid bilayer. RMSD analysis shows that AQP1 is the most flexible channel protein. The more rigid PfAQP and GlpF are characterized by the presence of additional salt-bridge and cation-π interactions. Moreover, certain loops have stronger interactions with transmembrane helices in both PfAQP and GlpF. To further enhance our understanding we performed three additional simulations by creating in-silico mutants in GlpF and AQP1 that either disrupted the existing interactions or resulted in new interactions. The results from these simulations clearly demonstrated the important role of certain non-covalent interactions in solute transport and hints that aquaporin channel transport can be regulated in multiple ways.