Inosine triphosphatase (ITPA) is an enzyme that catalyzes the conversion of non-canonical purine nucleotides inosine triphosphate(ITP), deoxy ITP (dITP), and xanthosine triphosphate(XTP) to the corresponding nucleoside monophosphate and pyrophosphate. Deficient ITPA activity can cause the accumulation of ITP, dITP, and XTP, which may be introduced into RNA and DNA resulting in possible genetic mutation and instability. The ITPA variants P-32 and R-178 are associated to epileptic encephalopathy and purine analog drug toxicity. The human ITPA is a homodimer which consists of central beta-sheet with two lobes having mixed alpha-beta structures. In this study, we used molecular dynamics (MD) simulation to understand the effect of P32 and R178 mutations on the structure of human ITPA. The results for more 300 ns simulations show the influence of point mutation on the 3D structure and flexibility of ITPA. The analysis of the simulation trajectories also revealed the detail conformation change of the ITPA mutant. This study is an important starting point for protein engineering design of ITPA.

Insights from molecular dynamics simulations into the structure and dynamics of ITPA mutants

255th National Meeting (2018)

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