In silico analyses of deleterious missense SNPs of human apolipoprotein E3

Abstract

ApoE3 is the major chylomicron apolipoprotein, binding in a specific liver peripheral cell receptor, allowing transport and normal catabolism of triglyceride-rich lipoprotein constituents. Point mutations in ApoE3 have been associated with Alzheimer’s disease, type III hyperlipoproteinemia, atherosclerosis, telomere shortening and impaired cognitive function. Here, we evaluate the impact of missense SNPs in APOE retrieved from dbSNP through 16 computational prediction tools, and further evaluate the structural impact of convergent deleterious changes using 100 ns molecular dynamics simulations. We have found structural changes in four analyzed variants (Pro102Arg, Arg132Ser, Arg176Cys and Trp294Cys), two of them (Pro102Arg and Arg176Cys) being previously associated with human diseases. In all cases, except for Trp294Cys, there was a loss in the number of hydrogen bonds between CT and NT domains that could result in their detachment. In conclusion, data presented here could increase the knowledge of ApoE3 activity and be a starting point for the study of the impact of variations on APOE gene.

Insights into the structural and dynamical changes of spike glycoprotein mutations associated with SARS-CoV-2 host receptor binding

“…The single amino acid mutation is directly proportional to the functional contacts of protein/receptor within the complex diseases and also known for its quick drug response (Schreiner et al, 2011). Many cases of studies have been reported for the successful application of mutation associated strategy to understand the individual drug response, phenotypic variability at genetic state in personalized medicine, as this area of study utilizes sequence, structural, physicochemical and stereo-chemical properties of amino acids (Pires et al, 2017;Schreiner et al, 2011).…”

Using an integrative machine learning approach utilising homology modelling to clinically interpret genetic variants: CACNA1F as an exemplar

“…A number of in silico tools can be used for interpreting the effects of sequence variants, both in research and in clinical laboratory settings. Four commonly used tools include Sorting Intolerant From Tolerant (SIFT, [13]) which uses a sequence homology-based method, polymorphism phenotyping v2 (PolyPhen2, [14]) which utilises a sequence and structure-based approach, combined annotation dependent depletion (CADD, [15]) which uses a supervised learning method, and consensus deleteriousness score (CONDEL, [16]) which uses a consensus-based approach [17]. The latest version of CONDEL combines the predictions of two other tools, mutation assessor [18] and the Functional Analysis Through Hidden Markov Models ( [19]) using weighted averaging.…”

Mutational analysis on predicting the impact of high-risk SNPs in human secretary phospholipase A2 receptor (PLA2R1)

“…Additionally, the authors have added post translational modification analysis to more validate the findings 17 . One more study identified the SNPs in interleukin-8 (IL-8) gene for this purpose the study combines the structural functional analysis along with the docking studies to identify the effect of potential variants on protein-protein interactions 18 . Taking this into consideration, the present study aimed to explore the structural and functional impact of missense coding SNPs of PLA2R1 by using various computational tools.…”