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 II

69-POS Board 22 Computational Studies on Hsp70 Unify Experimental Findings and Reveal Additional Significant Residues for Further Study Gizem Ozbaykal , Canan Atilgan, Ali Rana Atilgan. Sabanci University, Istanbul, Turkey. An Hsp70 protein orchestrates allosteric communication between its nucleotide and substrate binding domains. We employ the structure of E. coli DnaK , Hsp70, 1 and we propose the following methodology: (i) We arbitrarily pick an amino acid in the protein structure; (ii) we substitute the residue by an alanine and we minimize the altered structure; (iii) we record the positional changes that take place following minimization. This methodology quantifies to what extent a single-point mutation would affect each residue in the protein. We obtain the average displacement of a residue by averaging the displacements when all others are substituted by alanine. Moreover, we obtain the change in average reachability of residues by calculating the difference in average path length of a residue between the mutated and original networked structure. We propose that the sites of functional importance, such as those associated with binding or folding display large deviations from their original state. A cluster of residues (T428, Q471, and D490-E496) at the substrate binding cavity show pronounced differences which are confirmed by experimental studies. 2 Furthermore, we calculate the betweenness centrality to distinguish residues most traversed when a walk is performed between any two arbitrary residues in the networked structure. The walk is biased, based-on residue-residue contact energies. Results emphasize residues N522, D526, C529 and E530 located at the lid which plays role in an opening-closing movement so as to bind and release the substrate. They are found to affect the chaperone activities of Hsp70 either by changing its substrate binding affinity or by modifying folding mechanism. 3 1 Kityk et al., Mol Cell,48,863(2012). 2 Swain et al., Mol Cell,26,27(2007). 3 Burkholder, et al., PNAS, 93,10632(1996); Suh et al., PNAS,95,15223(1998); Moro etal., J Biol Chem,279,19600(2004); Slepenkov et al., Biochemistry,42,5867(2004).

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