Elucidation of the structural dynamics of mutations in PHB2 protein associated with growth suppression and cancer progression

Abstract

Prohibitin is a multifunctional protein that plays an important role in numerous cellular processes. Membrane-associated mitochondrial prohibitin complex is made up of two subunits, PHB1 and PHB2 which are ubiquitously expressed and analogous to each other. High levels of prohibitin expression have consequently been found in esophageal cancer, endometrial adenocarcinoma, gastric cancer, hepatocellular carcinoma, breast cancer and bladder cancer. The aim of this study is to analyse two-point mutation PHB2_MT1(I → A) and PHB2_MT2(I → P), their effect on PHB2 protein and its effect on formation of mitochondrial complex. It is a residual level study, based on current experimental validation. To establish the effects of the two-point mutations, computational approaches such as molecular modelling, molecular docking, normal mode simulation, molecular dynamics simulations and MM/GBSA were used. An analysis of the energy dynamics of both unbound and complex proteins was conducted to elucidate how mutations impact the energy distribution of PHB2. Our study confirmed that the two mutations decreased the overall stability of PHB2. This was evidenced by heightened atomic fluctuations within the mutated region, accompanied by elevated deviations observed in RMSD and Rg values. Furthermore, these mutations were correlated with a decline in the organization of secondary structural elements. The mutations in PHB2_MT1 and PHB2_MT2 resulted in formation a less stable prohibitin complex. Thus, PHB1 and PHB2 may act as molecular target or novel biomarkers for therapeutic intervention in numerous forms of malignancies.