Computational Screening and Molecular Dynamic Simulation of Breast Cancer Associated Deleterious Non-Synonymous Single Nucleotide Polymorphisms in TP53 Gene

Breast cancer is one of the most common cancers among the women around the world. Several genes are known to be responsible for conferring the susceptibility to breast cancer. Among them, TP53 is one of the major genetic risk factor which is known to be mutated in many of the breast tumor types. TP53 mutations in breast cancer are known to be related to a poor prognosis and chemo resistance. This renders them as a promising molecular target for the treatment of breast cancer. In this study, we present a computational based screening and molecular dynamic simulation of breast cancer associated deleterious non-synonymous single nucleotide polymorphisms in TP53. We have predicted three deleterious coding non-synonymous single nucleotide polymorphisms rs11540654 (R110P), rs17849781 (P278A) and rs28934874 (P151T) in TP53 with a phenotype in breast tumors using computational tools SIFT, Polyphen-2 and MutDB. We have performed molecular dynamics simulations to study the structural and dynamic effects of these TP53 mutations in comparison to the wild-type protein. Results from our simulations revealed a detailed consequence of the mutations on the p53 DNA-binding core domain that may provide insight for therapeutic approaches in breast cancer.     

Computational Prediction and Analysis of Breast Cancer Targets for 6-Methyl-1, 3, 8-Trichlorodibenzofuran

Breast cancer is one of the most known cancer types caused to the women around the world. Dioxins on the other hand are a wide range of chemical compounds known to cause the effects on human health. Among them, 6-Methyl-1,3,8-trichlorodibenzofuran (MCDF) is a relatively non toxic prototypical alkyl polychlorinated dibenzofuran known to act as a highly effective agent for inhibiting hormone-responsive breast cancer growth in animal models. In this study, we have developed a multi-level computational approach to identify possible new breast cancer targets for MCDF. We used PharmMapper Server to predict breast cancer target proteins for MCDF. Search results showed crystal Structure of the Antagonist Form of Glucocorticoid Receptor with highest fit score and AutoLigand analysis showed two potential binding sites, site-A and site-B for MCDF. A molecular docking was performed on these two sites and based on binding energy site-B was selected. MD simulation studies on Glucocorticoid receptor-MCDF complex revealed that MCDF conformation was stable at site-B and the intermolecular interactions were maintained during the course of simulation. In conclusion, our approach couples reverse pharmacophore analysis, molecular docking and molecular dynamics simulations to identify possible new breast cancer targets for MCDF.     

A systematic strain selection approach for halotolerant and halophilic bioprocess development: a review

Halotolerant and halophilic microorganisms have potential applications in a number of very relevant environmental and industrial bioprocesses, from wastewater treatment to production of value-added chemicals. While numerous microbial strains have been identified and studied in the literature, the number of those successfully used in industrial applications is comparatively small. Literature is abundant in terms of characterisation of specific strains under a microbiology perspective; however, there is a need for studies tackling the selection of strains for bioprocess applications. This review presents a database of over 200 halophilic and halotolerant prokaryote strains compiled from taxonomic microbiological resources and classified by trophic groups as well as by their salinity, pH and temperature tolerance and optimum ranges, all under a process development perspective. In addition to this database, complementary systematic approaches for the selection of suitable strains for a given trophic activity and environmental conditions are also presented. Both the database and the proposed selection approaches together constitute a general tool for process development that allows researchers to systematically search for strains capable of specific substrate degradations under specific conditions (pH, T, salinity). Many exiting established halotolerant and halophilic environmental and industrial bioprocesses appear to have been developed following strategies in line with the systematic approaches proposed here.     

D224V and S128Y mutation in FSHRED influence thumb movement differentially: An intricate insight gained by short-term molecular dynamics simulation

Follicle-stimulating hormone-follicle-stimulating hormone receptor (FSH-FSHR) interaction is one of the most thoroughly studied signaling pathways primarily because of being implicated in sexual reproduction in mammals by way of maintaining gonadal function and sexual fertility. Despite material advances in understanding the role of point mutations, their mechanistic basis in FSH-FSHR signaling is still confined to mystically altered behavior of sTYS335 (sulfated tyrosine) yet lacking a substantial theory. To understand the structural basis of receptor modulation, we choose two behaviorally contradicting mutations, namely S128Y (activating) and D224Y (inactivating), found in FSH receptor responsible for ovarian hyperstimulation syndrome and ovarian dysgenesis, respectively. Using short-term molecular dynamics simulations, the atomic scale investigations reveal that the binding pattern of sTYS with FSH and movement of the thumb region of FSHR show distinct contrasting patterns in the two mutants, which supposedly could be a critical factor for differential FSHR behavior in activating and inactivating mutations.     

Increased ventricular repolarization heterogeneity in patients with ventricular arrhythmia vulnerability and cardiomyopathy: a human in vivo study

Increased repolarization heterogeneity can provide the substrate for reentrant ventricular arrhythmias in animal models of cardiomyopathy. We hypothesized that ventricular repolarization heterogeneity is also greater in patients with cardiomyopathy and ventricular arrhythmia vulnerability (inducible ventricular tachycardia or positive microvolt T wave alternans, VT/TWA) compared with a similar patient population without ventricular arrhythmia vulnerability (no VT/TWA). Endocardial and epicardial repolarization heterogeneity was measured in patients with (n = 12) and without (n = 10) VT/TWA by using transvenous 26-electrode catheters placed along the anteroseptal right ventricular endocardium and left ventricular epicardium. Local activation times (AT), activation-recovery intervals (ARI), and repolarization times (RT) were measured from unipolar electrograms. Endocardial RT dispersion along the apicobasal ventricle was greater (P < 0.005) in patients with VT/TWA than in those without VT/TWA because of greater ARI dispersion (P < 0.005). AT dispersion was similar between the two groups. Epicardial RT dispersion along the apicobasal ventricle was greater (P < 0.05) in patients with VT/TWA than in those without VT/TWA because of greater ARI dispersion (P < 0.05). AT dispersion was similar between the two groups. A plot of AT as a function of ARI revealed an inverse linear relationship for no VT/TWA such that progressively later activation was associated with progressively shorter ARI. The AT-ARI relationship was nonlinear in VT/TWA. In conclusion, patients with cardiomyopathy and VT/TWA have greater endocardial and epicardial repolarization heterogeneity than those without VT/TWA without associated conduction slowing. The steep repolarization gradients in VT/TWA may provide the substrate for functional conduction block and reentrant ventricular arrhythmias.     

Influence of cation–π interactions to the structural stability of prokaryotic and eukaryotic translation elongation factors

We have investigated the role of cation–π interactions on translation elongation factors. In our investigation, an average of four significant cation–π interactions were found, that is, an average of one cation–π interaction per 44 residues in the ten elongation factors were observed. The analysis on the influence of short (<±4), medium (>±4 to <±20) and long (>20) range contacts showed that cation–π interactions are mainly formed by medium and long-range contacts. Arg-Tyr pair was found largest in number but energetic contribution of Arg-Trp pair was found most. Preferred secondary structural conformation analysis of the residues involved in cation–π interaction indicates that the cationic Arg prefers to be in helix and Lys having equal probability for helix and strand, whereas the aromatic Phe and Trp were found mostly in helix while Tyr in strand regions. The cation–π interaction residues involved in these proteins were found highly conserved with 48.86% residues having conservation score of ≥6. Analysis of secondary structure preference of the energetically significant cation–π residues in different solvent accessible range indicates that most of the π residues are found buried or partially buried whereas cationic residues were found mostly at the protein surface. The results presented in this study will be useful for structural stability studies in translation elongation factors.