Impact of Single amino acid Polymorphisms in Protein-Protein interactions in tumorigenic cluster A and cluster B of VHL: Computational molecular dynamics

The VHL tumour suppressor gene codes for von-Hippel Lindau (VHL) protein which acts by association with Elongin C and Hypoxia Inducing Factor-1 alpha (HIF). Two functional sub-domains in the protein model of VHL contain binding sites for these proteins. Alpha domain of VHL protein contains the binding site for Elongin C (tumorigenic cluster A) whereas; the beta domain contains the binding site for HIF-1 alpha (tumorigenic cluster B). The complex formation between VHL, Elongin C and HIF1 alpha protein is crucial for the regulation of ubiquitin dependent proteolysis of oncogenic proteins. Henceforth defects in the complex formation may lead to von-Hippel Lindau disease. A majority of VHL disease causing mutations found to occur in these binding sites are highly conserved. In this computational analysis, we predicted the functional effect of Single amino acid Polymorphisms (SAPs) in VHL-interacting proteins with the aid of pathogenicity and protein stability predictors. Furthermore, molecular dynamic behavior of the native and mutant protein complexes were analyzed by using different parameters such as Root Mean Square Deviation, Root Mean Square Fluctuation and Hydrogen bonding variations Molecular dynamics studies were performed for five variants S111R, H115Q and W117C, L158V and C162F of VHL protein that occur in the Elongin-C and HIF-1 alpha protein binding domain. Through the molecular dynamics simulations analysis, we observed that the stability and flexibility between VHL-Elongin-C and VHL-HIF-1 complexes were altered. Our strategy may be valuable for understanding SAP effects on protein-protein interactions with function and their role in human genetic diseases, linking structure function relationship and also for the development of novel pharmacological strategies. Proceedings IWBBIO 2014. Granada 7-9 April, 2014 1705 2