Modeling of Biomolecular Systems Interactions, Dynamics, and Allostery: Bridging Experiments and Computations - September 10-14, 2014, Istanbul, Turkey

Modeling of Biomolecular Systems Interactions, Dynamics, and Allostery Poster Session I

39-POS Board 39 Comparative Study of Functional Dynamics in Mutant von Hippel-Lindau Tumor Suppressor Protein Structures Tandaç Fürkan Güçlü , Pemra Özbek, A. Nevra Özer. Department of Bioengineering, Marmara University, Goztepe, Istanbul, Turkey. The von Hippel-Lindau cancer syndrome, which is an autosomal dominant disease characterized by development of tumors in different organs including renal cell carcinoma, is associated with the mutations on the von Hippel-Lindau tumor suppressor protein (pVHL). The mutation on pVHL bound to ElonginC-ElonginB complex activates the production of the hypoxia inducible factor (HIF) and the vascular endothelial growth factor (VEGF) which in turn leads to tumor growth. In this work, mutant structures of the pVHL bound to Elongin C and HIF which were experimentally demonstrated to have variable stabilities and binding affinities are built for further computational structural dynamics analysis. The dynamics of the wild-type, the designed Y98N mutant, and the designed Y98N-G123F double mutant structures are assessed comparatively using the Anisotropic Network Model (ANM), which predicts the magnitudes and directionalities of the collective motions by a harmonic vibrational analysis based on normal modes. In a previous Molecular Dynamics (MD) study, Y98N mutant was shown to be associated with the VHL disease whereas Y98N-G123F double mutant was shown to exhibit similar stability with the wild-type structure. Here, the analyses of the orientation of fluctuations and the correlations between fluctuations in the most cooperative functional modes of ANM also show that the wild-type dynamic behavior is similar to the Y98N-G123F double mutant compared to the Y98N mutant structure. The directions of fluctuations differ mainly around the dynamically key regions, i.e. the hinge regions in the minima of the mode shapes, justifying that the dynamic behavior of hinge residues should correlate with the functioning of proteins. Overall, this study would help in the drug design studies for the VHL disease by explaining the structural dynamics basis of molecular recognition and evolutionary optimization in the pVHL system.

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