Membrane remodeling due to mixture of multiple curvature proteins: Insights from mesoscopic continuum modeling

We present an extension of the Monte Carlo based mesoscopic membrane model where the membrane is represented as a dynamically triangulated surface and the proteins are modeled as anisotropic inclusions formulated as in-plane nematic field variables adhering to the deformable elastic sheet. The local orientation of the nematic field lies in the local tangent plane of the membrane and is free to rotate in this plane. Protein-membrane interactions are modeled as anisotropic spontaneous curvatures of the membrane and protein-protein interactions are modeled by the splay and bend terms of Frank's free energy for nematic liquid crystals. In the extended model, we have augmented the Hamiltonian to study membrane deformation due to a mixture of multiple types of curvature generating proteins. This feature opens the door for understanding how multiple different kinds of curvature-generating proteins may be working in a coordinated manner to induce desired membrane morphologies. For example, among other things, we study membrane deformations and tubulation due to a mixture of positive and negative curvature proteins as mimics of various proteins from BAR domain family working together for curvature formation and stabilization. We also study the effect of membrane anisotropy, which manifests as membrane localization and differential binding affinity of a given curvature protein, leading to insights into the tightly regulated cargo sorting and transport processes. Our simulation results show different morphologies of deformed vesicles that depend on the curvatures and densities of the participating proteins as well as on the protein-protein and membrane-proteins interactions.

Network visualisation of synthetic biology designs

Visualising the complex information captured by synthetic biology designs is still a major challenge. The popular glyph approach where each genetic part is displayed on a linear sequence allows researchers to generate diagrams and visualise abstract designs, but only represents a single, static representation that results in visualisation that is not specific to the requirements of a user resulting in a one-size-fits-all visualisation. We developed a network visualisation technique that automatically turns all design information into a graph, displaying otherwise hidden data. The structure of the resulting graphs can be dynamically adjusted according to specific visualisation requirements, such as highlighting proteins, interactions or hierarchy. Since biological systems have an inherent affinity with network visualisation, we advocate for adopting this approach to standardise and automate the representation of complex information.

Molecular Docking Study of the Potential Relevance of the Natural Compounds Isoflavone and Myricetin to COVID-19

The 2019 novel coronavirus (2019-nCoV) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread rapidly from its origin in Wuhan City, Hubei Province, China, to the rest of the world. The efficacy of herbal treatment in the control of contagious disease was demonstrated during the 2003 outbreak of severe acute respiratory syndrome (SARS). Natural compound used for this study were isoflavone and myricetin. Molecular docking was performed to analyze binding mode of the compounds towards 12 proteins related to COVID-19. The prediction shows that isoflavone and myricetin have moderate probability of antiviral activity. All of the docked compounds occupied the active sites of the proteins related to COVID-19. Based on QSAR and molecular docking, interactions were predicted with 10 out of 12 potential COVID-19 proteins for myricetin and with 9 out of 12 proteins interactions for isoflavone. A potential disease alleviating action is suggested for isoflavone and myricetin in the context of COVID-19 infection.

Study on the Mechanism of Ginkgo Seeds in Treating Bronchitis by Network Pharmacology

In recent years, with the global environmental deterioration and air pollution, the incidence of bronchitis has increased year by year, and the sales of anti-bronchitis drugs are growing rapidly, mainly due to the long treatment cycle and the difficulty of curing. Developing available traditional Chinese medicines with significant curative effect against bronchitis would be a promising strategy; for instance, Ginkgo seeds, as the fruit of natural plant ginkgo, has been used in ancient times to cure coughs. However, the detailed mechanism of curing cough has not been shown yet. Investigate the mechanism of Ginkgo Semen in the treatment of bronchitis by establishing a series of molecular networks including active ingredients-targets, proteins interactions, biological functions, pathway, and biological processes of targets. In this study, the main active ingredients of Ginkgo seeds and the potential targets related to bronchitis could be obtained by retrieving corresponding database. The molecular docking study between active molecules and protein targets was performed by Glide 6.6. Subsequently, a total of forty potential targets were manually selected. Based on this, the ingredients-target network was constructed using Cytoscape software, as well as proteins interactions network combing with the String database. Finally, the molecular biological function, metabolic pathway, and biological processes of these forty targets were analyzed by Clue GO plug-in. The results indicated that these protein targets were closely related to lipid transport, positive regulation of DNA replication, cAMP metabolic pathway, and other processes, which played a vital role in the treatment of bronchitis by mediating interleukin 17, fluid shear stress and atherosclerosis, asthma, renin secretion, p53, and other signaling pathways. Among these targets, the two protein ALB (Albumin) and DHRS2 (Dehydrogenase 2) can interact with compounds more frequently, and the top three compounds ranked by the docking scores were amentoflavone, (+)-catechin-5-O-glucoside, and liquiritin, implying that these compounds might be used for the treatment of bronchitis. It is obvious that the pharmacological effect of Ginkgo seeds on bronchitis displayed a characteristic of multi-components, multi-targets, and multi-pathways. Nevertheless, the two protein targets and three compounds derived from Ginkgo seeds could be further used for the explanation for Ginkgo seeds in curing bronchitis. This research can provide a scientific basis for studying on the anti-bronchitis mechanism of Ginkgo seeds.

Molecular profiling of Neprilysin expression and its interactions with SARS-CoV-2 spike proteins to develop evidence base pharmacological approaches for therapeutic intervention

Neprilysin due to its peptidase activity is involved in several physiological and pathological processes. Recently our group has reported the association of neprilysin with angiotensin-converting enzyme 2 (ACE2) network proteins which facilitate the entry of SARS-COV2 virus. The potential role of neprilysin beyond its peptidase activity is not known. Using the established sequence analysis and molecular docking tools, this study evaluated the molecular profile of neprilysin interaction with SARS-COV2 virus proteins. Human neprilysin protein showed a significant sequence similarity with SARS-COV2 spike protein, which was further confirmed by observation of considerable interaction in the molecular docking. Human neprilysin protein was also found to additionally interact with SARS-COV2 proteins facilitating virus replication. The potential of neprilysin inhibitors (Sacubitril and Sacubitrilat) to interfere with neprilysin and SARS-COV2 proteins interactions was assessed. The neprilysin inhibitors showed binding efficacy within therapeutically feasible concentration range (1 to 150 uM). This study while reporting a novel role of neprilysin as potential receptor for SARS-COV2 virus, highlights the merit in assessing clinical efficacy of neprilysin inhibitors for the management of SARS-COV2 infection.

A review of the interaction between anthocyanins and proteins

Anthocyanins have good physiological functions, but they are unstable. The interaction between anthocyanins and proteins can improve the stability, nutritional and functional properties of the complex. This paper reviews the structural changes of complex of anthocyanins interacting with proteins from different sources. By circular dichroism (CD) spectroscopy, it was found that the contents of α-helix (from 15.90%−42.40% to 17.60%−52.80%) or β-sheet (from 29.00%−50.00% to 29.40%−57.00%) of the anthocyanins–proteins complex increased. Fourier transform infrared spectroscopy showed that the regions of amide I (from 1627.87−1641.41 cm−1 to 1643.34−1651.02 cm−1) and amide II (from 1537.00−1540.25 cm−1 to 1539.00−1543.75 cm−1) of anthocyanins–proteins complex were shifted. Fluorescence spectroscopy showed that the fluorescence intensity of the complex decreased from 150−5100 to 40−3900 a.u. The thermodynamic analysis showed that there were hydrophobic interactions, electrostatic and hydrogen bonding interactions between anthocyanins and proteins. The kinetic analysis showed that the half-life and activation energy of the complex increased. The stability, antioxidant, digestion, absorption, and emulsification of the complex were improved. This provides a reference for the study and application of anthocyanins and proteins interactions.

Molecular dynamics approach for capturing calixarenes--proteins interactions: the case of cytochrome c

Here, we propose a molecular dynamics investigation of the supramolecular association of sulfonatedcalix-[8]-arenes to cytochrome c. The binding sites prone to interactions with sulfonated calixarenescan be identified without prior knowledge of the X-ray structure, and the binding free energiesestimated by molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) post-analysis arefound to be in neat agreement with the isothermal titration calorimetry (ITC) measurements The per-residuedecomposition reveals the detailed picture of this electrostatically-driven association and notably therole of the arginine R13 as a bridge residue between the two main anchoring sites. In addition,the analysis of the residue behavior by means of a supervised machine learning protocol unveils the formation of an hydrogen bond network far from the binding sites, increasing the rigidity of theprotein.

Molecular dynamics approach for capturing calixarenes--proteins interactions: the case of cytochrome c

Here, we propose a molecular dynamics investigation of the supramolecular association of sulfonatedcalix-[8]-arenes to cytochrome c. The binding sites prone to interactions with sulfonated calixarenescan be identified without prior knowledge of the X-ray structure, and the binding free energiesestimated by molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) post-analysis arefound to be in neat agreement with the isothermal titration calorimetry (ITC) measurements The per-residuedecomposition reveals the detailed picture of this electrostatically-driven association and notably therole of the arginine R13 as a bridge residue between the two main anchoring sites. In addition,the analysis of the residue behavior by means of a supervised machine learning protocol unveils the formation of an hydrogen bond network far from the binding sites, increasing the rigidity of theprotein.

MicroRNA-Independent Modulation of DICER1 Expression by hAgo2

ABSTRACT Many proteins, including DICER1 and hAgo2, are involved in the biogenesis of microRNAs (miRNAs). Whether hAgo2 regulates DICER1 expression is unknown. Exogenously overexpressed hAgo2 suppressed DICER1 expression at the levels of both protein and mRNA, and the reduction in hAgo2 expression enhanced DICER1 expression. Precursor miRNA processing mediated by DICER1 was also modulated by hAgo2. However, hAgo2 protein did not suppress DICER1 promoter activity. Therefore, hAgo2 protein probably regulates DICER1 expression at the posttranscriptional level. Indeed, hAgo2 protein inhibited the reporter assay of the DICER1 mRNA 3′ untranslated region (3′-UTR). Previous reports have demonstrated that miRNAs (e.g., let-7 and miR-103/107) inhibited DICER1 expression posttranscriptionally. However, hAgo2 still suppressed DICER1 expression in the cells depleted of these miRNAs. Moreover, the reporter activities of the DICER1 mRNA 3′-UTR without these miRNA binding sites were still suppressed by hAgo2. Therefore, in addition to an miRNA-dependent pathway, hAgo2 can also modulate DICER1 expression through an miRNA-independent mechanism. Downregulation of DICER1 expression was further proven to be dependent on both hAgo2 and AUF1 proteins. Interactions of hAgo2 and AUF1 proteins were demonstrated by the coimmunoprecipitation assay. As expected, hAgo2 could not suppress the DICER1 mRNA 3′-UTR reporter with a mutation in the potential AUF1-binding site. Thus, downregulation of DICER1 expression through the 3′-UTR requires both hAgo2 and AUF1.