Retinitis pigmentosa (RP) refers to a group of debilitating, hereditary disorders that cause severe visual impairment in as many as 1.5 million patients worldwide. Rhodopsin mutations account for > 25% of the autosomal dominant form of the disease (ADRP). Forty artificial and ADRP-associated mutations located in the second extracellular loop (EL2) that folds into a twisted beta-hairpin were screened through replica exchange molecular dynamics (REMD) simulations using the FACTS implicit solvent model. According to in vitro experiments, ADRP-linked mutants fail to express at the plasma membrane and/or to reconstitute with 11-cis-retinal, indicative of variable defects in protein folding and/or stability. The computational protocol was first probed on the protein G C-terminal beta-hairpin, proving the effectiveness of the implicit solvent model in reproducing the free energy landscape of beta-hairpin formation. Eight out of the 40 EL2 mutants resulted in misfolding effects on the native beta-hairpin structure, consistent with in vitro evidence that they all share severe impairments in folding/expression. Five mutants displayed moderate misfolding attitudes, whereas the remaining 27 mutants, overall characterized by milder effects on rhodopsin expression, did not perturb significantly the conformational behavior of the native beta-hairpin but are expected to exert variably disturbing effects on the native interactions of the loop with the chromophore and/or the surrounding receptor domains. Collectively, the results of this study add structural insight to the poorly resolved biochemical behavior of selected class II ADRP mutations, a fundamental step toward an understanding of the atomistic causes of the disease.

Computational Screening of Rhodopsin Mutations Associated with Retinitis Pigmentosa / Felline, Angelo Nicola; M., Seeber; F., Rao; Fanelli, Francesca. - In: JOURNAL OF CHEMICAL THEORY AND COMPUTATION. - ISSN 1549-9618. - ELETTRONICO. - 5:9(2009), pp. 2472-2485. [10.1021/ct900145u]

Computational Screening of Rhodopsin Mutations Associated with Retinitis Pigmentosa

FELLINE, Angelo Nicola;FANELLI, Francesca
2009

Abstract

Retinitis pigmentosa (RP) refers to a group of debilitating, hereditary disorders that cause severe visual impairment in as many as 1.5 million patients worldwide. Rhodopsin mutations account for > 25% of the autosomal dominant form of the disease (ADRP). Forty artificial and ADRP-associated mutations located in the second extracellular loop (EL2) that folds into a twisted beta-hairpin were screened through replica exchange molecular dynamics (REMD) simulations using the FACTS implicit solvent model. According to in vitro experiments, ADRP-linked mutants fail to express at the plasma membrane and/or to reconstitute with 11-cis-retinal, indicative of variable defects in protein folding and/or stability. The computational protocol was first probed on the protein G C-terminal beta-hairpin, proving the effectiveness of the implicit solvent model in reproducing the free energy landscape of beta-hairpin formation. Eight out of the 40 EL2 mutants resulted in misfolding effects on the native beta-hairpin structure, consistent with in vitro evidence that they all share severe impairments in folding/expression. Five mutants displayed moderate misfolding attitudes, whereas the remaining 27 mutants, overall characterized by milder effects on rhodopsin expression, did not perturb significantly the conformational behavior of the native beta-hairpin but are expected to exert variably disturbing effects on the native interactions of the loop with the chromophore and/or the surrounding receptor domains. Collectively, the results of this study add structural insight to the poorly resolved biochemical behavior of selected class II ADRP mutations, a fundamental step toward an understanding of the atomistic causes of the disease.
2009
5
9
2472
2485
Computational Screening of Rhodopsin Mutations Associated with Retinitis Pigmentosa / Felline, Angelo Nicola; M., Seeber; F., Rao; Fanelli, Francesca. - In: JOURNAL OF CHEMICAL THEORY AND COMPUTATION. - ISSN 1549-9618. - ELETTRONICO. - 5:9(2009), pp. 2472-2485. [10.1021/ct900145u]
Felline, Angelo Nicola; M., Seeber; F., Rao; Fanelli, Francesca
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/625420
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