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(2009), pp. 2472-2485.
|Data di pubblicazione:||2009|
|Titolo:||Computational Screening of Rhodopsin Mutations Associated with Retinitis Pigmentosa|
|Autore/i:||FELLINE, Angelo Nicola; M., Seeber; F., Rao; FANELLI, Francesca|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1021/ct900145u|
|Codice identificativo ISI:||WOS:000269488300028|
|Codice identificativo Scopus:||2-s2.0-73349083086|
|Codice identificativo Pubmed:||26616627|
|Citazione:||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(2009), pp. 2472-2485.|
|Tipologia||Articolo su rivista|
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