Molecular Dynamic Simulation Reveals Structure Differences in APOL1 Variants and Implication in Pathogenesis of Chronic Kidney Disease.

BACKGROUND: According to observational studies, two polymorphisms in the apolipoprotein L1 (APOL1) gene have been linked to an increased risk of chronic kidney disease (CKD) in Africans. One polymorphism involves the substitution of two amino-acid residues (S342G and I384M; known as G1), while the other involves the deletion of two amino-acid residues in a row (N388 and Y389; termed G2). Despite the strong link between APOL1 polymorphisms and kidney disease, the molecular mechanisms via which these APOL1 mutations influence the onset and progression of CKD remain unknown. METHODS: To predict the active site and allosteric site on the APOL1 protein, we used the Computed Atlas of Surface Topography of Proteins (CASTp) and the Protein Allosteric Sites Server (PASSer). Using an extended molecular dynamics simulation, we investigated the characteristic structural perturbations in the 3D structures of APOL1 variants. RESULTS: According to CASTp's active site characterization, the topmost predicted site had a surface area of 964.892 Å2 and a pocket volume of 900.792 Å3. For the top three allosteric pockets, the allostery probability was 52.44%, 46.30%, and 38.50%, respectively. The systems reached equilibrium in about 125 ns. From 0-100 ns, there was also significant structural instability. When compared to G1 and G2, the wildtype protein (G0) had overall high stability throughout the simulation. The root-mean-square fluctuation (RMSF) of wildtype and variant protein backbone Cα fluctuations revealed that the Cα of the variants had a large structural fluctuation when compared to the wildtype. CONCLUSION: Using a combination of different computational techniques, we identified binding sites within the APOL1 protein that could be an attractive site for potential inhibitors of APOL1. Furthermore, the G1 and G2 mutations reduced the structural stability of APOL1.

Computational construction of a glycoprotein multi-epitope subunit vaccine candidate for old and new South-African SARS-CoV-2 virus strains.

The discovery of a new SARS-CoV-2 virus strain in South Africa presents a major public health threat, therefore contributing to increased infections and transmission rates during the second wave of the global pandemic. This study lays the groundwork for the development of a novel subunit vaccine candidate from the circulating strains of South African SARS-CoV-2 and provides an understanding of the molecular epidemiological trend of the circulating strains. A total of 475 whole-genome nucleotide sequences from South Africa submitted between December 1, 2020 and February 15, 2021 available at the GISAID database were retrieved based on its size, coverage level and hosts. To obtain the distribution of the clades and lineages of South African SARS-CoV-2 circulating strains, the metadata of the sequence retrieved were subjected to an epidemiological analysis. There was a prediction of the cytotoxic T lymphocytes (CTL), Helper T cells (HTL) and B-cell epitopes. Furthermore, there was allergenicity, antigenicity and toxicity predictions on the epitopes. The analysis of the physicochemical properties of the vaccine construct was performed; the secondary structure, tertiary structure and B-cell 3D conformational structure of the vaccine construct were predicted. Also, molecular binding simulations and dynamics simulations were adopted in the prediction of the vaccine construct's stability and binding affinity with TLRs. Result obtained from the metadata analysis indicated lineage B.1.351 to be in higher circulation among various circulating strains of SARS-CoV-2 in South Africa and GH has the highest number of circulating clades. The construct of the novel vaccine was antigenic, non-allergenic and non-toxic. The Instability index (II) score and aliphatic index were estimated as 41.74 and 78.72 respectively. The computed half-life in mammalian reticulocytes was 4.4 h in vitro, for yeast and in E. coli was >20 h and >10 h in vivo respectively. The grand average of hydropathicity (GRAVY) score is estimated to be -0.129, signifying the hydrophilic nature of the protein. The molecular docking indicates that the vaccine construct has a high binding affinity towards the TLRs with TLR 3 having the highest binding energy (-1203.2 kcal/mol) and TLR 9 with the lowest (-1559.5 kcal/mol). These results show that the vaccine construct is promising and should be evaluated using animal model.

MAVSCOT: A fuzzy logic-based HIV diagnostic system with indigenous multi-lingual interfaces for rural Africa.

HIV still constitutes a major public health problem in Africa, where the highest incidence and prevalence of the disease can be found in many rural areas, with multiple indigenous languages being used for communication by locals. In many rural areas of the KwaZulu-Natal (KZN) in South Africa, for instance, the most widely used languages include Zulu and Xhosa, with only limited comprehension in English and Afrikaans. Health care practitioners for HIV diagnosis and treatment, often, cannot communicate efficiently with their indigenous ethnic patients. An informatics tool is urgently needed to facilitate these health care professionals for better communication with their patients during HIV diagnosis. Here, we apply fuzzy logic and speech technology and develop a fuzzy logic HIV diagnostic system with indigenous multi-lingual interfaces, named Multi-linguAl HIV indigenouS fuzzy logiC-based diagnOstic sysTem (MAVSCOT). This HIV multilingual informatics software can facilitate the diagnosis in underprivileged rural African communities. We provide examples on how MAVSCOT can be applied towards HIV diagnosis by using existing data from the literature. Compared to other similar tools, MAVSCOT can perform better due to its implementation of the fuzzy logic. We hope MAVSCOT would help health care practitioners working in indigenous communities of many African countries, to efficiently diagnose HIV and ultimately control its transmission.