Four mutations (G90D, T94I, A292E, A295V) have been identified as genetic links to congenital stationary night blindness (CSNB), in which the human GPCR rhodopsin without retinal binding become intrinsically activated due to the mutations. Although the high resolution structure of G90D is available, that of the other three are not yet available. In this study, the homology models of T94I, A292E, A295V and the wild-type (WT) were built from the G90D crystal structure. Five systems were subjected to 2 μs molecular dynamics simulations. Our Root Mean Square Fluctuation (RMSF) data show that the RMSF pattern of G90D, T941 and A295V significantly differs from that of the WT and A295V. Additionally, there are short β-strands in all four mutants (G90D, T94I, A292E, and A295V) that are non-existent in the wild-type. There are kinks in the α-helical structure of the CSNB mutants that are less prevalent in the WT. Insights from this study will ideally lead to develop pharmacophores as therapeutic targets for night blindness.

Shedding light on the conformational changes leading to intrinsic activation of four night blindness mutations G90D, T94I, A292E, A295V on the human GPCR rhodopsin: A molecular dynamics simulation study

254th National Meeting (2017)

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