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Computational investigation of O2 diffusion through an intra-molecular tunnel in AlkB; influence of polarization on O2 transport

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Abstract

E. Coli AlkB catalyzes the direct dealkylation of various alkylated bases in damaged DNA. The diffusion of molecular oxygen to the active site in AlkB is an essential step for the oxidative dealkylation activity. Despite detailed studies on the stepwise oxidation mechanism of AlkB, there is no conclusive picture of how O2 molecules reach the active site of the protein. Yu et al. (Nature, 439, 879) proposed the existence of an intra-molecular tunnel based on their initial crystal structures of AlkB. We have employed computational simulations to investigate possible migration pathways inside AlkB for O2 molecules. Extensive molecular dynamics (MD) simulations, including explicit ligand sampling and potential of mean force (PMF) calculations, have been performed to provide a microscopic description of the O2 delivery pathway in AlkB. Analysis of intra-molecular tunnels using the CAVER software indicates two possible pathways for O2 to diffuse into the AlkB active site. Explicit ligand sampling simulations suggests that only one of these tunnels provides a viable route. The free energy path for an oxygen molecule to travel along each of these tunnels has been determined with AMBER and AMOEBA. Both PMFs indicate passive transport of O2 from the surface of the protein. However, the inclusion of explicit polarization shows a very large barrier for diffusion of the co-substrate out of the active site, compared with the non-polarizable potential. In addition, our results suggest that the mutation of a conserved residue along the tunnel, Y178, has dramatic effects on the dynamics of AlkB and on the transport of O2 along the tunnel.

Graphical abstract: Computational investigation of O2 diffusion through an intra-molecular tunnel in AlkB; influence of polarization on O2 transport

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Publication details

The article was received on 03 Mar 2017, accepted on 03 Jul 2017 and first published on 05 Jul 2017


Article type: Edge Article
DOI: 10.1039/C7SC00997F
Citation: Chem. Sci., 2017, Advance Article
  • Open access: Creative Commons BY license
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    Computational investigation of O2 diffusion through an intra-molecular tunnel in AlkB; influence of polarization on O2 transport

    H. Torabifard and G. A. Cisneros, Chem. Sci., 2017, Advance Article , DOI: 10.1039/C7SC00997F

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