Zinc and Its Critical Role in Retinitis pigmentosa: Insights from DFT/SMD Calculations

Abstract

Metal cations are required for the proper function of a great amount of biological processes, as they are indispensable cofactors participating in up to 40% of the active sites of the proteins. In the case of some diseases, however, metal cations could exhibit a dual function. As an example, the role of the zinc cation in the development of Retinitis pigmentosa could be given. Experimental works indicate the loss of thermostability of the rhodopsin protein, subjected to the combination oftypical for the diseasemutations and increased quantity of Zn 2+ . Two structural networks in the intradiscal domain surrounding His100 and His195 are supposed to be susceptible to pathophysiological changes in trace metal concentrations. From a thermodynamic point of view, it is of particular interest to decipher the foundations of the observed outcome, as well as to closely characterize the intimate interactions between the "native" cation and the building amino acid residues of the studied centers. Therefore, the powerful, but fundamentally limited, tools of computational chemistry were applied on simplified models of rhodopsin metal centers in order to shed light on the following aspects: (1) what is the preferred geometry of the Zn 2+ -containing complexes with the amino acid ligands from the binding pockets; (2) what is the role of the mutations for the interactions between Zn 2+ and the examined centers; (3) could other divalent cations such as Ca 2+ and Cu 2+ substitute for the native zinc; (4) how does the dielectric constant of the environment affect the processes? The obtained results illuminate some aspects of the zinc coordination to amino acid residues and zinc biochemistry related to the presumed pathogenesis of Retinitis pigmentosa.

Binding of Captopril and Bioactive Tripeptides Val-Pro-Pro and Ile-Pro-Pro to Angiotensin I-Converting Enzyme (ACE I): Insights from DFT

“…B3LYP/6-31+G(3d,p) level of theory was chosen for all molecular electronic structure calculations in the gas phase, ε=1, and in protein environment, ε=4. This functional/basis set combination has been recently shown to be reliable in studying the function of the zinc cation in two centers of rhodopsin [11]. Monosodium salts of Captopril, Val-Pro-Pro and Ile-Pro-Pro inhibitors were optimized and these structures were used to build up models of HEXXH motif bound to inhibitor molecules after a displacement of a water molecule (Figure 2).…”

Case Report: The First Reported Concurrence of Wilson Disease and Bilateral Retinitis Pigmentosa

“…Metal cations are required in numerous biological processes, as in the pathogenesis of RP. For example, the role of zinc cation in the development of RP has been illustrated to be related to the loss of thermostability of the rhodopsin protein and zinc coordination to amino acid residues ( 33 ). Severe brain iron deposition is also implicated in the pathogenesis of neurodegenerative disorders and inherited diseases.…”

Effects of high‐energy multicore ferrocene‐based catalysts on the thermal decomposition of ammonium perchlorate

“…[18] The C, N, and H atoms were optimized using 6-311G* basis set, [19] and the Fe atoms were optimized using LANL2DZ basis set, [20] dichloromethane as solvent and SMD as solvent model. [21] 3 | RESULTS AND DISCUSSION…”