Mucormycosis is an invasive fungal infection with considerably high mortality rates in immunocompromised individuals. Due to COVID-19 pandemic, the disease has resurfaced recently and lack of appropriate antifungals resulted in a poor outcome in patients. The iron uptake mechanism in Rhizopus delemar, the predominant causal agent is crucial for its survival and pathogenesis in human host. The current study focuses on the structural dynamics of high affinity iron permease (Ftr1) which act as a virulence factor in this fatal fungal disease. Ftr1 is a transmembrane protein which is responsible for the transport of Fe 3+ ion from the extracellular milieu to the cytoplasm under iron-starving conditions in Rhizopus. In this work, the three-dimensional modelling of Ftr1 was carried out and it was found to possess seven transmembrane helices with N-terminal lying in the extracellular region and C-terminal in the intracellular region. Moreover, the present study delineates the interaction of glutamic acid residues, found in the REGLE motif of the fourth transmembrane helix with Fe 3+. The molecular dynamics (MD) simulation study revealed that the glycine present in the motif destabilizes the helix thereby bringing E157 closer to the positively charged ion. Understanding the interaction between Fe 3+ ion and Ftr1 would be helpful in designing effective small molecule drugs against this novel therapeutic target for treating mucormycosis.

Glucose-Methanol-Choline (GMC) family enzymes are very important in catalyzing the oxidation of a wide range of structurally diverse substrates. Enzymes that constitute the GMC family, share a common tertiary fold but < 25% sequence identity. Cofactor FAD, FAD binding signature motif, and similar structural scaffold of the active site are common features of oxidoreductase enzymes of the GMC family. Protein functionality mainly depends on protein three-dimensional structures and dynamics. In this study, we used the normal mode analysis method to search the intrinsic dynamics of GMC family enzymes. We have explored the dynamical behavior of enzymes with unique substrate catabolism and active site characteristics from different classes of the GMC family. Analysis of individual enzymes and comparative ensemble analysis of enzymes from different classes has shown conserved dynamic motion at FAD binding sites. The present study revealed that GMC enzymes share a strong dynamic similarity (Bhattacharyya coefficient >90% and root mean squared inner product >52%) despite low sequence identity across the GMC family enzymes. The study predicts that local deformation energy between atoms of the enzyme may be responsible for the catalysis of different substrates. This study may help that intrinsic dynamics can be used to make meaningful classifications of proteins or enzymes from different organisms.