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

2-POS Board 2 A Computational Approach to Iron Release Dynamics in Human Serum Transferrin Haleh Abdizadeh , Ali Rana Atilgan, Canan Atilgan. Sabanci University, Istanbul, Turkey. Human serum transferrin(hTF) transports ferric ions in blood serum and delivers them to cells via receptor mediated endocytosis[1]. Transferrin is folded into two homologous lobes; each is further divided into two similar sized subdomains. Four major populations, namely holo, two monoferric and apo hTf are suggested, based-on the iron occupancy of the deep cleft within the subdomains in each lobe[2]. Many factors affect distribution of conformational substates of hTf, including pH, and anion concentration. The mechanisms leading to conformational changes prior to iron release are not known. The specialized role of the two lobes and whether communication between them leads to a controllable release mechanism is also debated in literature[3]. Here, we study the dynamics of the full structure, separate lobes, and monoferric states of holo form of hTf under the nearly neutral pH conditions in blood serum and the more acidic one in the endosome. Results are in remarkable agreement with experimental observations and underscore the distinguishing effect of pH on the dynamics of hTf[4]. Furthermore, in a grand total of 1 μs molecular dynamics simulations of holo form of hTf at different pH values, residue fluctuations and cross-correlations elucidate the cross talk between the two lobes communicated by the bridging linker. Finally, we use a combination of solvent accessible surface area, Poisson- Boltzmann and radial distribution function calculations to decipher the so-called kinetically significant anion binding(KISAB) sites at the exposed surface of the protein. Some KISAB sites have been determined experimentally and were proposed to contribute to the iron release rate by interacting with non-synergistic anions[5]. [1]M.W. Hentze et al.,Cell,142,24-38(2010). [2]A.B. Mason et al. Protein Expres. Purif.,23,142-150(2001). [3]S.L. Byrne et al. J. Mol. Biol.,396,130-140(2010). [4]A.N. Steere et al. Biochim. Biophysic. Acta-General Subj.,1820,326-333(2012). [5]S.A. Kretchmar, K.N. Raymond, Inorg. Chem.,27,1436-1441(1988).

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