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Modeling, Docking, and Simulation of the Major Facilitator Superfamily

John Holyoake ^*, Victoria Caulfeild ^*, Stephen A. Baldwin  and Mark S. P. Sansom ^*

^* Department of Biochemistry, University of Oxford, Oxford, United Kingdom; and Astbury Centre for Structural Molecular Biology, Institute of Membrane and Systems Biology, University of Leeds, Leeds, United Kingdom

Correspondence: Address reprint requests and inquiries to Mark Sansom, E-mail: mark.sansom{at}bioch.ox.ac.uk.

X-ray structures are known for three members of the Major Facilitator Superfamily (MFS) of membrane transporter proteins, thus enabling the use of homology modeling to extrapolate to other MFS members. However, before employing such models for, e.g., mutational or docking studies, it is essential to develop a measure of their quality. To aid development of such metrics, two disparate MFS members (NupG and GLUT1) have been modeled. In addition, control models were created with shuffled sequences, to mimic poor quality homology models. These models and the template crystal structures have been examined in terms of both static and dynamic indicators of structural quality. Comparison of the behavior of modeled structures with the crystal structures in molecular dynamics simulations provided a metric for model quality. Docking of the inhibitor forskolin to GLUT1 and to a control model revealed significant differences, indicating that we may identify accurate models despite low sequence identity between target sequences and templates.

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