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AbstractThe GBA1gene encodes for the lysosomal enzyme glucocerebrosidase (GCase), which maintains glycosphingolipid homeostasis and regulates the autophagy process. Genomic variants of GBA1are associated with Goucher disease; however, several heterozygous variants of GBA (E326K, T369M, N370S, L444P) are frequent high-risk factors for Parkinson’s disease (PD). The underlying mechanism of these variants has been revealed through functional and patient-centered research, but the structural and dynamical aspects of these variants have not yet been thoroughly investigated. In the current study, we used a thorough computational method to pinpoint the structural changes that GBA underwent because of genomic variants and drug binding mechanisms. According to our findings, PD-linked nsSNP variants of GBA showed structural variation and abnormal dynamics when compared to wild-typ. The docking analysis demonstrated that the mutants E326K, N370S, and L444P have higher binding affinities for Ambroxol. Root means square deviation (RMSD), Root mean square fluctuation analysis (RMSF), and MM-GBSA analysis confirmed that the Ambroxol are more stable in the binding site of N370S and L444P, and that their binding affinities are stronger as compared to the wild-type and T369M variants of GBA. The evaluation of hydrogen bonds and the calculation of the free binding energy provided additional evidence in favor of this conclusion. When docked with Ambroxol, GBA demonstrated an increase in binding affinity and catalytic activity. Understanding the therapeutic efficacy and potential against the aforementioned changes in the GBA will be beneficial in order to use more efficient methods for developing novel drugs.

AbstractLysosomal enzymes degrade cellular macromolecules, while their inactivation causes human hereditary metabolic disorders. Mucopolysaccharidosis IVA (MPS IVA; Moquio A syndrome) is one of the lysosomal storage disorders caused by a defective Galactosamine-6-sulfatase (GalN6S) enzyme. In several populations, disease incidence is elevated due to missense mutations brought on by non-synonymous allelic variation in the GalN6S enzyme. Here, we studied the effect of non-synonymous single nucleotide polymorphism (nsSNPs) on the structural dynamics of the GalN6S enzyme and its binding with N-acetylgalactosamine (GalNAc) using all-atom molecular dynamics simulation and an essential dynamics approach. Consequently, in this study, we have identified three functionally disruptive mutations in domain-I and domain-II, that is, S80L, R90W, and S162F, which presumably contribute to post-translational modifications. The study delineated that both domains work cooperatively, and alteration in domain II (S80L, R90W) leads to conformational changes in the catalytic site in domain-I, while mutation S162F mainly provokes higher residual flexibility of domain II. These results show that these mutations impair the hydrophobic core, implying that Morquio A syndrome is caused by misfolding of the GalN6S enzyme. The results also show the instability of the GalN6S-GalNAc complex upon substitution. Overall, the structural dynamics resulting from point mutations give the molecular rationale for Moquio A syndrome and, more importantly, the Mucopolysaccharidoses (MPS) family of diseases, re-establishing MPS IVA as a protein-folding disease.Communicated by Ramaswamy H. Sarma

This paper proposes a novel energy dissipation low reinforced concrete (RC) shear wall to improve the seismic performance of the high-rise building. The novel energy dissipation low RC shear wall composes of shear wall, inner several vertical gaps and some built-in new lead dampers. In the novel shear wall, the inner lead dampers can produce a marked effect on energy dissipation and shear transmission. This paper first presents the simulation studies of lead dampers, including the simulation method and the simulation analysis. Based on the above study results, the following contents use ABAQUS software to study the seismic performances of the new energy dissipation shear wall, including the damage patterns, hysteresis curves, stiffness degradation and energy dissipation capacity. The analysis results show the proposed shear wall has well seismic performance. Meanwhile, the ductility of the proposed shear wall is higher than that of the conventional low shear wall. The bearing capacity is higher than that of the shear wall with vertical gaps. But the energy dissipation capacity decreases with the increase of the axial pressure ratio under a large axial pressure ratio. Especially, the number and the arrangement of lead dampers have an obvious effect on the seismic performance.