Molecular Dynamics Simulations Helps to Rationalize CopB Mutations and their Relationships to Wilson Disease

Abstract

The regulation of copper levels is central to physiology. Mutations in the ATP7B copper transporter are known to lead to Wilson's disease in humans. How these mutations lead to the disease is not fully characterized at a molecular level. An excellent model system for exploring the changes in structure and dynamics for Wilson disease mutations for the ATP binding domain is provided by CopB from A. fulgidus. This domain has high sequence similarity with the P-, N-domains and hinge regions of ATP7B. Mutations to each region have previously been characterized by in vitro experimental measurements such as ATPase assays and intrinsic tryptophan fluorescence. In this presentation we highlight a net ∼5 μs of implicit and explicit solvent simulations conducted on the National supercomputer resource XSEDE (Stampede, Kraken, Keeneland and Lonestar) of the CopB wild-type and 13 Wilsons disease mutations found across each of these three regions. Solvent accessible surface area measurements, H-bonds analysis and schlitter entropy calculations showed that the mutations induced changes in the dynamics of the Closed conformations of CopB with respect to the Open structure revealing conformational transitions at different rates about the hinge region. While the mutations in the P and N-domains caused mild to moderate deviations with respect to the WT, the mutations in the Hinge region caused significant deviations. The results shed new light on how the disease mutations impact on conformational change, on ATP-binding, and on phosphorylation within these domains.