Network and Atomistic Simulations Unveil the Structural Determinants of Mutations Linked to Retinal Diseases

A number of incurable retinal diseases causing vision impairments derive from alterations in visual phototransduction. Unraveling the structural determinants of even monogenic retinal diseases would require network-centered approaches combined with atomistic simulations.The transducin G38D mutant associated with the Nougaret Congenital Night Blindness (NCNB) was thoroughly investigated by both mathematical modeling of visual phototransduction and atomistic simulations on the major targets of the mutational effect.Mathematical modeling, in line with electrophysiological recordings, indicates reduction of phosphodiesterase 6 (PDE) recognition and activation as the main determinants of the pathological phenotype. Sub-microsecond molecular dynamics (MD) simulations coupled with Functional Mode Analysis improve the resolution of information, showing that such impairment is likely due to disruption of the PDEγ binding cavity in transducin. Protein Structure Network analyses additionally suggest that the observed slight reduction of theRGS9-catalyzed GTPase activity of transducin depends on perturbed communication between RGS9 and GTP binding site. These findings provide insights into the structural fundamentals of abnormal functioning of visual phototransduction caused by a missense mutation in one component of the signaling network. This combination of network-centered modeling with atomistic simulations represents a paradigm for future studies aimed at thoroughly deciphering the structural determinants of genetic retinal diseases. Analogous approaches are suitable to unveil the mechanism of information transfer in any signaling network either in physiological or pathological conditions.Author Summary: Incurable retinal diseases causing vision impairments may be due to spontaneous mutations in one component of the visual phototransduction signaling network. Such alterations include the transducin single point mutation G38D associated with the Nougaret Congenital Night Blindness (NCNB). We combined a systems biology approach with atomistic simulations to gain insights into the structural fundamentals of the NCNB disease. Consistent with in vitro evidence, mathematical modeling suggests reduced effector recognition and activation as the main determinants of the pathological phenotype. Sub-microsecond molecular dynamics simulations improve the resolution of information, suggesting that such impairment is likely due to disruption of the effector binding cavity. Atomistic simulations also suggest that the observed slight reduction of the RGS9-catalyzed GTPase activity of transducin depends on perturbed inter-protein communication involving the nucleotide. The study highlighted manifold effects of a single point pathogenic mutation, thus paving the way for analogous studies towards a thorough understanding of the structural determinants of genetic retinal diseases.