Abstract
Crystallins are ubiquitous, however, prevalence is seen in eye lens. Eye lens crystallins are long-lived and structural intactness is required for maintaining lens transparency and protein solubility. Mutations in crystallins often lead to cataract. In this study, we performed mutations at specific sites of M-crystallin, a close homologue of eye lens crystallin and studied by using replica exchange molecular dynamics simulation with generalized Born implicit solvent model. Mutations were made on the Ca2+ binding residues (K34D and S77D) and in the hydrophobic core (W45R) which is known to cause congenital cataract in homologous γD-crystallin. The chosen mutations caused large motion of the N-terminal Greek key, concomitantly broke the interlocking Greek keys interactions and perturbed the compact core resulting in several folded and partially unfolded states. Partially unfolded states exposed large hydrophobic patches that could act as precursors for self-aggregation. Accumulation of such aggregates is the potential cause of cataract in homologous eye lens crystallins.
Highlights
Crystallins are ubiquitous, prevalence is seen in eye lens
Stability comes from specific arrangement of the double Greek key motifs. βγ-crystallins from microbial origin undergo further stabilization upon binding to C a2+ while eye lens crystallins are stable without C a2+
In order to understand the effect of mutations at X 1 position in M-crystallin, we carried out K34D and S77D mutations (Fig. 1B)
Summary
Crystallins are ubiquitous, prevalence is seen in eye lens. Eye lens crystallins are longlived and structural intactness is required for maintaining lens transparency and protein solubility. Unfolded states exposed large hydrophobic patches that could act as precursors for self-aggregation Accumulation of such aggregates is the potential cause of cataract in homologous eye lens crystallins. Similar mutation from Ser to Arg in the canonical motif even stabilizes an intrinsically disordered βγ-crystallin, Hahellin in the absence of Ca2+ studied by employing replica exchange molecular dynamics simulations (REMD) with generalized Born (GB) implicit solvent model[16]. There is an increase in α-helical contain in GB REMD simulation compared to experiment and explicit solvent REMD s imulation[21] In another example, the C-terminal β-hairpin of protein G was studied with GB implicit solvent which resulted in non-native conformational states in the lowest free energy minimum while in explicit solvent simulation, native hairpin was in the lowest free energy minimum[23]. The arrangement of two Greek key motifs takes place in such a way that three of the four strands of a Greek key motif form one β-sheet and the remaining one β-strand pairs with three β-strands from other Greek key motif forming the second β-sheet[9]
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