Model of Abnormal Chromophore-Protein Interaction for E181K Rhodopsin Mutation: Computer Molecular Dynamics Study

Abstract

The interaction of the 11-cis-retinal chromophore with the surrounding amino acid residues in the chromophore center of the rhodopsin protein has been investigated for the Е181К mutant form using molecular dynamics simulation. A comparative analysis of the arrangement of the amino acid residues in the chromophore center has been performed for both wild (native) and mutant rhodopsins. It is shown that for the Е181К mutant rhodopsin there is no proper binding of 11-cis-retinal with the surrounding amino acid residues. The distortion of the conformation states in the mutant rhodopsin molecule takes place in both the chromophore center and cytoplasmic domain. Our simulations suggest that a stable covalent linkage of 11-cis-retinal with the protein part (viz. opsin) of the rhodopsin molecule will not form. This, on the other hand, implies that the protein’s active site in the cytoplasmic domain, which is responsible for the G-protein binding (so-called transducin), may not be completely blocked.Based on our molecular simulation data, we discuss the possible correlation between retinitis pigmentosa pathogenesis and the structural and functional properties of the rhodopsin protein.

Multi‐scale simulation reveals that an amino acid substitution increases photosensitizing reaction inputs in Rhodopsins

“…This approach is supported by spectroscopic experiments and combined QM/MM calculations showing that spectral properties of lipid-membrane-solubilized rhodopsin from Bos taurus are preserved in non-membrane environments 36,37,68,69,85,86,[88][89][90] . This is in full agreement with the high similarity of the protein conformations in these environments, as observed in the short nanosecond time scale of 11-cis-retinal adaptation during MD simulations 37,89,91 . In fact, both in non-membrane and in membrane media, hWT also exhibits an absorption maximum of 493 -500 nm 92 , while a hypsochromic spectral shift (blue shift) has been described for its mutant hM207R out of membrane 36,37 , being a mislocalized rhodopsin completely absent from membrane in some cell lines 48 .…”