cometadata/datacite-titles-descriptions-related-identifiers huggingface dataset:
DOI: 10.6084/m9.figshare.12932819.v1
title: Ribonucleocapsid assembly/packaging signals in the genomes of the coronaviruses SARS-CoV and SARS-CoV-2: detection, comparison and implications for therapeutic targeting

description: The genomic ssRNA of coronaviruses is packaged within a helical nucleocapsid. Due to transitional symmetry of a helix, weakly specific cooperative interaction between ssRNA and nucleocapsid proteins leads to the natural selection of specific quasi-periodic assembly/packaging signals in the related genomic sequence. Such signals coordinated with the nucleocapsid helical structure were detected and reconstructed in the genomes of the coronaviruses SARS-CoV and SARS-CoV-2. The main period of the signals for both viruses was about 54 nt, that implies 6.75 nt per N protein. The complete coverage of the ssRNA genome of length about 30,000 nt by the nucleocapsid would need 4.4 × 10<sup>3</sup> N proteins, that makes them the most abundant among the structural proteins. The repertoires of motifs for SARS-CoV and SARS-CoV-2 were divergent but nearly coincided for different isolates of SARS-CoV-2. We obtained the distributions of assembly/packaging signals over the genomes with nonoverlapping windows of width 432 nt. Finally, using the spectral entropy, we compared the load from point mutations and indels during virus age for SARS-CoV and SARS-CoV-2. We found the higher mutational load on SARS-CoV. In this sense, SARS-CoV-2 can be treated as a ‘newborn’ virus. These observations may be helpful in practical medical applications and are of basic interest. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.12871824.v1
title: Insights into the structural and dynamical changes of spike glycoprotein mutations associated with SARS-CoV-2 host receptor binding

description: Novel Coronavirus or SARS-CoV-2 has received worldwide attention due to the COVID-19 pandemic, which originated in Wuhan, China leading to thousands of deaths to date. The SARS-CoV-2 Spike glycoprotein protein is one of the main focus of COVID-19 related research as it is a structural protein that facilitates its attachment, entry, and infection to the host cells. We have focused our work on mutations in two of the several functional domains in the virus spike glycoprotein, namely, receptor-binding domain (RBD) and heptad repeat 1 (HR1) domain. These domains are majorly responsible for the stability of spike glycoprotein and play a key role in the host cell attachment and infection. In our study, several mutations like R408I, L455Y, F486L, Q493N, Q498Y, N501T of RBD (319-591), and A930V, D936Y of HR1 (912-984) have been studied to examine its role on the spike glycoprotein native structure. Comparisons of MD simulations in the WT and mutants revealed a significant de-stabilization effect of the mutations on RBD and HR1 domains. We have investigated the impact of mapped mutations on the stability of the spike glycoprotein, before binding to the receptor, which may be consequential to its binding properties to the receptor and other ligands. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.12937574
title: A 200 nanoseconds all-atom simulation of the pH-dependent EF loop transition in bovine β-lactoglobulin. The role of the orientation of the E89 side chain

description: <i>In silico</i> molecular dynamics (MD) using crystallographic and NMR data was used to simulate the effects of the protonation state of E89 on the pH-dependent conformational rearrangement of the EF loop, also known as the Tanford transition, in a series of apo-β‐lactoglobulin (BLG) structures. Compared to existing studies these simulations were carried out over a much longer time scale (200 ns where the stability of the transition can be evaluated) and used an explicit water model. We considered eight different entries from the Brookhaven Protein Data Bank (PDB) separated into two groups. We observed that fixing the protonation state of E89 prompts the transition of the EF loop only when its side chain is oriented under the loop and into the entrance of the interior cavity. The motion of the EF loop occurs mostly as a step-function and its timing varies greatly from ∼ 20 ns to ∼170 ns from the beginning of the simulation. Once the transition is completed, the protein appears to reach a stable conformation as in a true two-state transition. We also observed novel findings. When the transition occurs, the hydrogen bond between E89 and S116 is replaced with a salt bridge with Lys residues in the βC-CD loop-βD motif. This electrostatic interaction causes the distortion of this motif as well as the protrusion of the GH loop into the aperture of the cavity with the result of limiting the increase of its contour area despite the rotation of the EF loop. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.12937574.v1
title: A 200 nanoseconds all-atom simulation of the pH-dependent EF loop transition in bovine β-lactoglobulin. The role of the orientation of the E89 side chain

description: <i>In silico</i> molecular dynamics (MD) using crystallographic and NMR data was used to simulate the effects of the protonation state of E89 on the pH-dependent conformational rearrangement of the EF loop, also known as the Tanford transition, in a series of apo-β‐lactoglobulin (BLG) structures. Compared to existing studies these simulations were carried out over a much longer time scale (200 ns where the stability of the transition can be evaluated) and used an explicit water model. We considered eight different entries from the Brookhaven Protein Data Bank (PDB) separated into two groups. We observed that fixing the protonation state of E89 prompts the transition of the EF loop only when its side chain is oriented under the loop and into the entrance of the interior cavity. The motion of the EF loop occurs mostly as a step-function and its timing varies greatly from ∼ 20 ns to ∼170 ns from the beginning of the simulation. Once the transition is completed, the protein appears to reach a stable conformation as in a true two-state transition. We also observed novel findings. When the transition occurs, the hydrogen bond between E89 and S116 is replaced with a salt bridge with Lys residues in the βC-CD loop-βD motif. This electrostatic interaction causes the distortion of this motif as well as the protrusion of the GH loop into the aperture of the cavity with the result of limiting the increase of its contour area despite the rotation of the EF loop. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.12871824
title: Insights into the structural and dynamical changes of spike glycoprotein mutations associated with SARS-CoV-2 host receptor binding

description: Novel Coronavirus or SARS-CoV-2 has received worldwide attention due to the COVID-19 pandemic, which originated in Wuhan, China leading to thousands of deaths to date. The SARS-CoV-2 Spike glycoprotein protein is one of the main focus of COVID-19 related research as it is a structural protein that facilitates its attachment, entry, and infection to the host cells. We have focused our work on mutations in two of the several functional domains in the virus spike glycoprotein, namely, receptor-binding domain (RBD) and heptad repeat 1 (HR1) domain. These domains are majorly responsible for the stability of spike glycoprotein and play a key role in the host cell attachment and infection. In our study, several mutations like R408I, L455Y, F486L, Q493N, Q498Y, N501T of RBD (319-591), and A930V, D936Y of HR1 (912-984) have been studied to examine its role on the spike glycoprotein native structure. Comparisons of MD simulations in the WT and mutants revealed a significant de-stabilization effect of the mutations on RBD and HR1 domains. We have investigated the impact of mapped mutations on the stability of the spike glycoprotein, before binding to the receptor, which may be consequential to its binding properties to the receptor and other ligands. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.12853416
title: Immunoinformatics and molecular dynamics studies to predict T-cell-specific epitopes of four <i>Klebsiella pneumoniae</i> fimbriae antigens

description: <i>Klebsiella pneumoniae</i> (<i>K. pneumoniae</i>) is a causative agent of severe infections in humans. There is no publically available vaccine for <i>K. pneumoniae</i> infections yet. Here, using comprehensive immunoinformatics methods, T-cell-specific epitopes of four type 1 fimbriae antigens of <i>K. pneumoniae</i> were predicted and evaluated as potential vaccine candidates. Both CD8+ (class I) and CD4+ (class II) T-cell-specific epitopes were predicted and the epitopes similar to human proteome were excluded. Subsequently, the windows of class-II epitopes containing class-I epitopes were determined. The immunogenicity, IFN-γ production and population coverage were also estimated. Using the 3D structure of HLA and epitopes, molecular docking was carried out. Two best epitopes were selected for molecular dynamics studies. Our prediction and analyses resulted in the several dominant epitopes for each antigen. The docking results showed that all selected epitopes can bind to their restricted HLA molecules with high affinity. The molecular dynamics results indicated the stability of system with minimum possible deviation, suggesting the selected epitopes can be promising candidates for stably binding to HLA molecules. Altogether, our results suggest that the selected T-cell-specific epitopes of <i>K. pneumoniae</i> fimbriae antigens, particularly the two epitopes confirmed by molecular dynamics, can be applied for vaccine development. However, the <i>in vitro</i> and <i>in vivo</i> studies are required to authenticate the results of the present study. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.12853416.v1
title: Immunoinformatics and molecular dynamics studies to predict T-cell-specific epitopes of four <i>Klebsiella pneumoniae</i> fimbriae antigens

description: <i>Klebsiella pneumoniae</i> (<i>K. pneumoniae</i>) is a causative agent of severe infections in humans. There is no publically available vaccine for <i>K. pneumoniae</i> infections yet. Here, using comprehensive immunoinformatics methods, T-cell-specific epitopes of four type 1 fimbriae antigens of <i>K. pneumoniae</i> were predicted and evaluated as potential vaccine candidates. Both CD8+ (class I) and CD4+ (class II) T-cell-specific epitopes were predicted and the epitopes similar to human proteome were excluded. Subsequently, the windows of class-II epitopes containing class-I epitopes were determined. The immunogenicity, IFN-γ production and population coverage were also estimated. Using the 3D structure of HLA and epitopes, molecular docking was carried out. Two best epitopes were selected for molecular dynamics studies. Our prediction and analyses resulted in the several dominant epitopes for each antigen. The docking results showed that all selected epitopes can bind to their restricted HLA molecules with high affinity. The molecular dynamics results indicated the stability of system with minimum possible deviation, suggesting the selected epitopes can be promising candidates for stably binding to HLA molecules. Altogether, our results suggest that the selected T-cell-specific epitopes of <i>K. pneumoniae</i> fimbriae antigens, particularly the two epitopes confirmed by molecular dynamics, can be applied for vaccine development. However, the <i>in vitro</i> and <i>in vivo</i> studies are required to authenticate the results of the present study. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.12927755
title: <i>In-silico</i> screening of plant-derived antivirals against main protease, 3CL<sup>pro</sup> and endoribonuclease, NSP15 proteins of SARS-CoV-2

description: Novel Coronavirus or SARS-CoV-2 outbreak has developed a pandemic condition all over the world. The virus is highly infectious and spreads by human to human local transmission mode. Till date, there is no vaccination or drugs been approved for the treatment by the World Health Organisation. Henceforth, the discovery of the potential drugs is an urgent and utmost requirement for the medical fraternity. Since, the side effects of plant-derived compounds will be lower compared to synthetic/chemical drugs. The Main protease (3CL<sup>pro</sup> or NSP5) and endoribonuclease (NSP15) proteins are necessity for viral replication and its survival in the host cell. In the present study, <i>in-silico</i> approach of drug development was used to search for potential antiviral plant-derived compounds as inhibitors against SARS-CoV-2 replication proteins. Eight plant-derived compounds of which the antiviral activity was known and available, and two reported drugs against SARS-CoV-2 selected for the molecular docking analysis. The docking results suggested that bisdemethoxycurcumin, demethoxycurcumin, scutellarin, quercetin and myricetin showed least binding energy, <i>i.e.,</i> greater than −6.5 Kcal/mol against 3CL<sup>pro</sup> and endoribonuclease of SARS-CoV-2. Further studies of ADME-Tox and bioavailability of drugs were also performed that exhibited efficient parameters of drug likeness. Molecular dynamics simulation calculations were performed for the most negative binding affinity of the compound to evaluate the dynamic behavior,and stability of protein-ligand complex. Our findings suggest that these compounds could be potential inhibitors of SARS‐CoV-2 main protease and endoribonuclease. However, further <i>in-vitro</i> and pre-clinical experiments would validate the potential inhibitors of SARS‐CoV‐2 proteins.
DOI: 10.6084/m9.figshare.12927755.v1
title: <i>In-silico</i> screening of plant-derived antivirals against main protease, 3CL<sup>pro</sup> and endoribonuclease, NSP15 proteins of SARS-CoV-2

description: Novel Coronavirus or SARS-CoV-2 outbreak has developed a pandemic condition all over the world. The virus is highly infectious and spreads by human to human local transmission mode. Till date, there is no vaccination or drugs been approved for the treatment by the World Health Organisation. Henceforth, the discovery of the potential drugs is an urgent and utmost requirement for the medical fraternity. Since, the side effects of plant-derived compounds will be lower compared to synthetic/chemical drugs. The Main protease (3CL<sup>pro</sup> or NSP5) and endoribonuclease (NSP15) proteins are necessity for viral replication and its survival in the host cell. In the present study, <i>in-silico</i> approach of drug development was used to search for potential antiviral plant-derived compounds as inhibitors against SARS-CoV-2 replication proteins. Eight plant-derived compounds of which the antiviral activity was known and available, and two reported drugs against SARS-CoV-2 selected for the molecular docking analysis. The docking results suggested that bisdemethoxycurcumin, demethoxycurcumin, scutellarin, quercetin and myricetin showed least binding energy, <i>i.e.,</i> greater than −6.5 Kcal/mol against 3CL<sup>pro</sup> and endoribonuclease of SARS-CoV-2. Further studies of ADME-Tox and bioavailability of drugs were also performed that exhibited efficient parameters of drug likeness. Molecular dynamics simulation calculations were performed for the most negative binding affinity of the compound to evaluate the dynamic behavior,and stability of protein-ligand complex. Our findings suggest that these compounds could be potential inhibitors of SARS‐CoV-2 main protease and endoribonuclease. However, further <i>in-vitro</i> and pre-clinical experiments would validate the potential inhibitors of SARS‐CoV‐2 proteins.
DOI: 10.6084/m9.figshare.12853380
title: <i>In vitro</i>, <i>in vivo</i> and <i>in silico</i> rationale for the muscle loss due to therapeutic drugs used in the treatment of <i>Mycobacterium tuberculosis</i> infection

description: Tuberculosis globally affects millions of people every year and is responsible for high rates of mortality and morbidity in tropical countries like India. The treatment of tuberculosis involves using the first line of drugs especially Isoniazid, Pyrazinamide, Streptomycin, Ethambutol and Rifampicin for treatment under the DOTS (Directly Observed Treatment Shots) regime which can last up to minimum of six months. These drugs although widely used against <i>Mycobacterium tuberculosis</i> has given rise to multi drug resistant (MDR) tuberculosis strain. It has been observed widely that prolonged drug treatment for tuberculosis patient has rendered several side effects that include increasing muscle wasting and malnutrition. In our study, we have investigated the role of these major tuberculosis drugs namely Rifampicin, Streptomycin, Isoniazid, Pyrazinamide, and Ethambutol on actin polymerization which are famously known to be a central player in the sarcomere region of the muscle in human body. For <i>in vitro</i> studies, we have used biophysical approaches such as 90° scattering assay (RLS), size exclusion chromatography (SEC), Dynamic light scattering (DLS), Circular dichroism spectroscopy (CD), Scanning electron microscopy (SEM), Transmission electron microscopy (TEM), kinetic analysis to understand the time taken to break down effect of above mentioned drugs on actin disruption. I<i>n vivo</i> analysis was carried out on yeast Δ<i>end3</i> mutants which are rich in F-actin filaments in order to understand the effect of the aforementioned drugs in rendering the muscle wasting phenomenon in tuberculosis. Furthermore, we also carried out <i>in silico</i> analysis to understand the probable modes of binding of these drugs on actin filaments. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.12853380.v1
title: <i>In vitro</i>, <i>in vivo</i> and <i>in silico</i> rationale for the muscle loss due to therapeutic drugs used in the treatment of <i>Mycobacterium tuberculosis</i> infection

description: Tuberculosis globally affects millions of people every year and is responsible for high rates of mortality and morbidity in tropical countries like India. The treatment of tuberculosis involves using the first line of drugs especially Isoniazid, Pyrazinamide, Streptomycin, Ethambutol and Rifampicin for treatment under the DOTS (Directly Observed Treatment Shots) regime which can last up to minimum of six months. These drugs although widely used against <i>Mycobacterium tuberculosis</i> has given rise to multi drug resistant (MDR) tuberculosis strain. It has been observed widely that prolonged drug treatment for tuberculosis patient has rendered several side effects that include increasing muscle wasting and malnutrition. In our study, we have investigated the role of these major tuberculosis drugs namely Rifampicin, Streptomycin, Isoniazid, Pyrazinamide, and Ethambutol on actin polymerization which are famously known to be a central player in the sarcomere region of the muscle in human body. For <i>in vitro</i> studies, we have used biophysical approaches such as 90° scattering assay (RLS), size exclusion chromatography (SEC), Dynamic light scattering (DLS), Circular dichroism spectroscopy (CD), Scanning electron microscopy (SEM), Transmission electron microscopy (TEM), kinetic analysis to understand the time taken to break down effect of above mentioned drugs on actin disruption. I<i>n vivo</i> analysis was carried out on yeast Δ<i>end3</i> mutants which are rich in F-actin filaments in order to understand the effect of the aforementioned drugs in rendering the muscle wasting phenomenon in tuberculosis. Furthermore, we also carried out <i>in silico</i> analysis to understand the probable modes of binding of these drugs on actin filaments. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.12928173
title: Deciphering inhibitory activity of flavonoids against tau protein kinases: a coupled molecular docking and quantum chemical study

description: Today, Alzheimer’s disease (AD) is one of the most important neurodegenerative disorders that affected millions of people worldwide. Hundreds of academic investigations highlighted the potential roles of natural metabolites in the cornerstone of AD prevention. Nevertheless, alkaloids are only metabolites that successfully showed promising clinical therapeutic effects on the prevention of AD. In this regard, other plant metabolites such as flavonoids are also considered as promising substances in the improvement of AD complications. The lack of data on molecular mode of action of flavonoids inside brain tissues, and their potential to transport across the blood-brain barrier, a physical hindrance between bloodstream and brain tissues, limited the large-scale application of these compounds for AD therapy programs. Herein, a coupled docking and quantum study was applied to determine the binding mode of flavonoids and three protein kinases involved in the pathogenesis of AD. The results suggested that all docked metabolites showed considerable binding affinity to interact with target receptors, but some compounds possessed higher binding energy values. Because docking simulation cannot entirely reveal the potential roles of ligand substructures in the interaction with target residues, quantum chemical analyses (QCAs) were performed to cover this drawback. Accordingly, QCAs determined that distribution of molecular orbitals have a pivotal function in the determination of the type of reaction between ligands and receptors; therefore, using such quantum chemical descriptors may correct the results of virtual docking outcomes to highlight promising backbones for further developments. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.12928173.v1
title: Deciphering inhibitory activity of flavonoids against tau protein kinases: a coupled molecular docking and quantum chemical study

description: Today, Alzheimer’s disease (AD) is one of the most important neurodegenerative disorders that affected millions of people worldwide. Hundreds of academic investigations highlighted the potential roles of natural metabolites in the cornerstone of AD prevention. Nevertheless, alkaloids are only metabolites that successfully showed promising clinical therapeutic effects on the prevention of AD. In this regard, other plant metabolites such as flavonoids are also considered as promising substances in the improvement of AD complications. The lack of data on molecular mode of action of flavonoids inside brain tissues, and their potential to transport across the blood-brain barrier, a physical hindrance between bloodstream and brain tissues, limited the large-scale application of these compounds for AD therapy programs. Herein, a coupled docking and quantum study was applied to determine the binding mode of flavonoids and three protein kinases involved in the pathogenesis of AD. The results suggested that all docked metabolites showed considerable binding affinity to interact with target receptors, but some compounds possessed higher binding energy values. Because docking simulation cannot entirely reveal the potential roles of ligand substructures in the interaction with target residues, quantum chemical analyses (QCAs) were performed to cover this drawback. Accordingly, QCAs determined that distribution of molecular orbitals have a pivotal function in the determination of the type of reaction between ligands and receptors; therefore, using such quantum chemical descriptors may correct the results of virtual docking outcomes to highlight promising backbones for further developments. Communicated by Ramaswamy H. Sarma