Molecular Modeling Approach Research Articles

Substrate specificity of branched chain amino acid aminotransferases: The substitution of glycine to serine in the active site determines the substrate specificity for α-ketoglutarate

A branched chain aminotransferase from Thermoproteus tenax has been identified, cloned, over-expressed and biochemically characterised. A molecular modelling approach has been used to predict the 3D structure allowing its comparison with other related enzymes. This enzyme has high similarity to a previously characterised aminotransferase from Thermoproteus uzoniensis however its substrate specificity shows key differences towards the substrate α-ketoglutarate. Examination of the active sites of the two related enzymes reveals a single amino acid substitution of a glycine residue to a serine residue which could be responsible for this difference. When Gly104 in T. tenax was mutated to a serine residue and the resultant enzyme characterised, this single amino acid change resulted in a dramatic reduction in activity towards α-ketoglutarate with an 18-fold reduction in Vmax and a 20-fold Km increase, resulting in a 370-fold lower catalytic efficiency. Structural comparisons between the two related Thermoproteus enzymes and another branched chain aminotransferase from Geoglobus acetivorans has revealed that the serine residue affects the flexibility of a key loop involved in catalysis. This subtle difference has provided further insight into our understanding of the substrate specificity of these industrially important enzymes.

Combining molecular modeling approaches to establish the chromatographic enantiomer elution order in the absence of pure enantiomeric standards: A study case with two tetracyclic quinolines

AbstractIn this study, the stereoisomers of two tetracyclic quinolines previously discovered as Pregnane X Receptor ligands were stereodiscriminated with a Chiralcel OD‐H column under normal‐phase conditions. The two compounds are characterized by a C/D cis ring junction and the co‐existence of four diastereoisomers for the presence of a further chiral center at the ring C. A mobile phase made‐up of n‐hexane/2‐PrOH – 99:1 (v/v) allowed to obtain the four peaks of each stereoisomer fully resolved with enantioseparation and enantioresolution factor values up to 2.98 and 11.16, respectively. Due to the lack of pure enantiomeric standards of known stereochemistry, an indirect protocol was successfully applied to define the enantiomeric elution order (EEO) under the identified optimal eluent conditions. This was possible by comparing experimental and theoretical Time‐Dependent Density Functional Theory (TD‐DFT) electronic circular dichroism spectra.In order to confirm the EEOs established through the ab initio calculations, molecular docking simulations were successfully performed with a nonameric model structure of the chiral selector. The results from the docking simulations were in perfect accordance with the results from the TD‐DFT study, thereby confirming the importance of performing multiple methods in the case of indirect attribution of the absolute configuration.

Screening of glycosylase activity on oxidative derivatives of methylcytosine: Pedobacter heparinus SMUG2 as a formylcytosine- and carboxylcytosine-DNA glycosylase

5-Methylcytosine (mC) is an epigenetic mark that impacts transcription, development, diseases including cancer and aging. The demethylation process involves Tet-mediated stepwise oxidation of mC to hmC, fC, or caC, excision of fC or caC by thymine-DNA glycosylase (TDG), and subsequent base excision repair. Thymine-DNA glycosylase (TDG) belongs to uracil-DNA glycosylase (UDG) superfamily, which is a group of enzymes that are initially found to be responsible for excising the deaminated bases from DNA and generating apurinic/apyrimidinic (AP) sites. mC oxidative derivatives may also be generated from Fenton chemistry and γ-irradiation. In screening DNA glycosylase activity in UDG superfamily, we identified new activity on fC- and caC-containing DNA in family 2 MUG/TDG and family 6 HDG enzymes. Surprisingly, we found a glycosylase SMUG2 from bacterium Pedobacter heparinus (Phe), a subfamily of family 3 SMUG1 DNA glycosylase, displayed catalytic activity towards not only DNA containing uracil, but also fC and caC. Given the sequence and structural differences between the family 3 and other family enzymes, we investigated the catalytic mechanism using mutational, enzyme kinetics and molecular modeling approaches. Mutational analysis and kinetics measurements identified I62, N63 and F76 of motif 1, and H205 of motif 2 in Phe SMUG2 as important catalytic residues, of which H205 of motif 2 played a critical role in catalyzing the removal of fC and caC. A catalytic model underlying the roles of these residues was proposed. The structural and catalytic differences between Phe SMUG2 and human TDG were compared by molecular modeling and molecular dynamics simulations. This study expands our understanding of DNA glycosylase capacity in UDG superfamily and provides insights into the molecular mechanism of fC and caC excision in Phe SMUG2.

Towards specie-specific ensemble vaccine candidates against mammarenaviruses using optimized structural vaccinology pipeline and molecular modelling approaches

Mammarena viruses are emerging pathogenic agents and cause hemorrhagic fevers in humans. These viruses accomplish host immune system evasion to replicate and spread in the host. There are only few available therapeutic options developed for Mammarena Virus (also called MMV). Currently, only a single candidate vaccine called Candid#1 is available against Junin virus. Similarly, the effective treatment Ribavirin is used only in Lassa fever treatments. Herein, immune-informatics pipeline has been used to annotate whole proteome of the seven human infecting Mammarena strains. The extensive immune based analysis reveals specie specific epitopes with a crucial role in immune response induction. This was achieved by construction of immunogenic epitopes (CTL “Cytotoxic T-Lymphocytes”, HTL “Helper T-Lymphocytes”, and B cell “B-Lymphocytes”) based vaccine designs against seven different Mammarena virus species. Furthermore, validation of the vaccine constructs through exploring physiochemical properties was performed to confirm experimental feasibility. Additionally, in-silico cloning and receptor based immune simulation was performed to ensure induction of primary and secondary immune response. This was confirmed through expression of immune factors such as IL, cytokines, and antibodies. The current study provides with novel vaccine designs which needs further demonstrations through potential processing against MMVs. Future studies may be directed towards advanced evaluations to determine the efficacy and safety of the designed vaccines through further experimental procedures.

Proline/Glycine residues of the PG-levels guide conformational changes along the transport cycle in the mitochondrial carnitine/acylcarnitine carrier (SLC25A20)

Mitochondrial carnitine/acylcarnitine carrier (CAC) is a member of the mitochondrial carrier (MC) family and imports acylcarnitine into the mitochondrial matrix in exchange for carnitine, playing a pivotal role in carnitine shuttle, crucial for fatty acid oxidation. The crystallized structure of CAC has not been solved yet, however, the availability of several in vitro/in silico studies, also based on the crystallized structures of the ADP/ATP carrier in the cytosolic-conformation and in the matrix-conformation, has made possible to confirm the hypothesis of the single-binding centered-gated pore mechanism for all the members of the MC family. In addition, our recent bioinformatics analyses allowed quantifying in silico the importance of protein residues of MC substrate binding region, of those involved in the formation of the matrix and cytosolic gates, and of those belonging to the Pro/Gly (PG) levels, proposed to be crucial for the tilting/kinking/bending of the six MC transmembrane helices, funneling the substrate translocation pathway. Here we present a combined in silico/in vitro analysis employed for investigating the role played by a group of 6 proline residues and 6 glycine residues, highly conserved in CAC, belonging to MC PG-levels. Residues of the PG-levels surround the similarly located MC common substrate binding region, and were proposed to lead conformational changes and substrate translocation, following substrate binding. For our analysis, we employed 3D molecular modeling approaches, alanine scanning site-directed mutagenesis and in vitro transport assays. Our analysis reveals that P130 (H3), G268 (H6) and G220 (H5), mutated in alanine, affect severely CAC transport activity (mutant catalytic efficiency lower than 5 % compared to the wild type CAC), most likely due to their major role in triggering CAC conformational changes, following carnitine binding. Notably, P30A (H1) and G121A (H3) CAC mutants, increase the carnitine uptake up to 217 % and 112 %, respectively, compared to the wild type CAC.

In silico study on the Hepatitis E virus RNA Helicase and its inhibition by silvestrol, rocaglamide and other flavagline compounds

Hepatitis E Virus (HEV) follows waterborne or zoonotic/foodborne transmission. Genotype 3 HEV infections are worldwide spread, especially in swine populations, representing an emerging threat for human health, both for farm workers and pork meat consumers. Unfortunately, HEV in vitro culture and analysis are still difficult, resulting in a poor understanding of its biology and hampering the implementation of counteracting strategies. Indeed, HEV encodes for only one non-structural multifunctional and multidomain protein (ORF1), which might be a good candidate for anti-HEV drugging strategies. In this context, an in silico molecular modelling approach that consisted in homology modelling to derive the 3D model target, docking study to simulate the binding event, and molecular dynamics to check complex stability over time was used. This workflow succeeded to describe ORF1 RNA Helicase domain from a molecular standpoint allowing the identification of potential inhibitory compounds among natural plant-based flavagline-related molecules such as silvestrol, rocaglamide and derivatives thereof. In the context of scouting potential anti-viral compounds and relying on the outcomes presented, further dedicated investigations on silvestrol, rocaglamide and a promising oxidized derivative have been suggested. For the sake of data reproducibility, the 3D model of HEV RNA Helicase has been made publicly available.

Structural insights into the inhibition of the nsP2 protease from Chikungunya virus by molecular modeling approaches.

Chikungunya virus (CHIKV) is the etiological agent of the Chikungunya fever which has spread worldwide. Clinically, this disease may lead to prolonged incapacitating joint pain that can compromise remarkably the patients' quality of life. However, there are no licensed vaccines or specific drugs to fight this infection yet, making the search for novel therapies an imperative need. In this scenario, the CHIKV nsP2 protease emerged as an attractive therapeutic target once this protein plays a pivotal role in viral replication and pathogenesis. Hence, we investigated the structural basis for the inhibition of this enzyme by using molecular docking and dynamics simulations. Compounds with inhibitory activities against CHIKV nsP2 protease determined experimentally were selected from the literature. Docking studies with a set of stereoisomers showed that trans isomers, but not cis ones, bound close to the catalytic dyad which may explain isomerism requirements to the enzyme's inhibition. Further, binding mode analyses of other known inhibitors revealed highly conserved contacts between inhibitors and enzyme residues like N1011, C1013, A1046, Y1079, N1082, W1084, L1205, and M1242. Molecular dynamics simulations reinforced the importance of some of these interactions and pointed to nonpolar interactions as the main forces for inhibitors' binding. Finally, we observed that true inhibitors exhibited lower structural fluctuation, higher ligand efficiency and did not induce significant changes in protein correlated motions. Collectively, our findings might allow discerning true inhibitors from false ones and can guide drug development efforts targeting the nsP2 protease to fight CHIKV infections in the future.

A theoretical study of CO2 capture by highly hydrophobic type III deep eutectic solvents

The properties of tetraoctylammonium chloride: decanoic acid (for 1: 2 molecular ratio) were studied using a molecular modeling approach to characterize its nanoscopic behavior and its performance for CO2 capturing purposes. The biological impact of the considered fluid was analyzed through docking studies on selected protein targets and their interaction with model lipid bilayers. The hydrogen bonding in the fluid was studied using quantum chemistry and topological analysis. The fluids' structuring was studied considering classical molecular dynamics simulations as a function of temperature, pressure, and CO2 content. The reported results allowed the complete nanoscopic characterization of the regarded eutectic fluid and the absorption and solvation of CO2, which shows how hydrophobic Deep Eutectic Solvents can be considered a suitable platform for carbon capture purposes.

Towards Molecular Understanding of the Functional Role of UbiJ-UbiK2 Complex in Ubiquinone Biosynthesis by Multiscale Molecular Modelling Studies.

Ubiquinone (UQ) is a polyisoprenoid lipid found in the membranes of bacteria and eukaryotes. UQ has important roles, notably in respiratory metabolisms which sustain cellular bioenergetics. Most steps of UQ biosynthesis take place in the cytosol of E. coli within a multiprotein complex called the Ubi metabolon, that contains five enzymes and two accessory proteins, UbiJ and UbiK. The SCP2 domain of UbiJ was proposed to bind the hydrophobic polyisoprenoid tail of UQ biosynthetic intermediates in the Ubi metabolon. How the newly synthesised UQ might be released in the membrane is currently unknown. In this paper, we focused on better understanding the role of the UbiJ-UbiK2 heterotrimer forming part of the metabolon. Given the difficulties to gain functional insights using biophysical techniques, we applied a multiscale molecular modelling approach to study the UbiJ-UbiK2 heterotrimer. Our data show that UbiJ-UbiK2 interacts closely with the membrane and suggests possible pathways to enable the release of UQ into the membrane. This study highlights the UbiJ-UbiK2 complex as the likely interface between the membrane and the enzymes of the Ubi metabolon and supports that the heterotrimer is key to the biosynthesis of UQ8 and its release into the membrane of E. coli.

Molecular dynamics simulations highlight the altered binding landscape at the spike-ACE2 interface between the Delta and Omicron variants compared to the SARS-CoV-2 original strain

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) B.1.1.529 variant (Omicron), represents a significant deviation in genetic makeup and function compared to previous variants. Following the BA.1 sublineage, the BA.2 and BA.3 Omicron subvariants became dominant, and currently the BA.4 and BA.5, which are quite distinct variants, have emerged. Using molecular dynamics simulations, we investigated the binding characteristics of the Delta and Omicron (BA.1) variants in comparison to wild-type (WT) at the interface of the spike protein receptor binding domain (RBD) and human angiotensin converting enzyme-2 (ACE2) ectodomain. The primary aim was to compare our molecular modelling systems with previously published observations, to determine the robustness of our approach for rapid prediction of emerging future variants. Delta and Omicron were found to bind to ACE2 with similar affinities (−39.4 and −43.3 kcal/mol, respectively) and stronger than WT (−33.5 kcal/mol). In line with previously published observations, the energy contributions of the non-mutated residues at the interface were largely retained between WT and the variants, with F456, F486, and Y489 having the strongest energy contributions to ACE2 binding. Further, residues N440K, Q498R, and N501Y were predicted to be energetically favourable in Omicron. In contrast to Omicron, which had the E484A and K417N mutations, intermolecular bonds were detected for the residue pairs E484:K31 and K417:D30 in WT and Delta, in accordance with previously published findings. Overall, our simplified molecular modelling approach represents a step towards predictive model systems for rapidly analysing arising variants of concern.

2‐Chloro‐5‐(1‐hydroxy‐3‐oxoisoindolin‐1‐yl)benzenesulfonamides as potential inhibitors of urease: Synthesis, in‐vitro and molecular modeling approach

AbstractThe present work is focused on the identification of 2‐chloro‐5‐(1‐hydroxy‐3‐oxoisoindolin‐1‐yl) benzenesulfonamides (5a–5k) Schiff bases as potent urease inhibitors. The rationale behind the urease activity was to introduce lead candidate for the treatment of GIT disorders including gastric and peptic ulcer and hepatic encephalopathy. The synthesized compounds exhibited excellent anti‐urease activity which was further supported by in‐silico investigations. Therefore, it can be suggested that these derivatives can be considered as a potential lead in future for synthesis of potent inhibitors.

In silico toxicity investigation of Methaqualone’s conjunctival, retinal, and gastrointestinal hemorrhage by molecular modelling approach

ABSTRACT Methaqualone was once used to treat insomnia as a hypnotic agent. Methaqualone, like other sedative–hypnotics, is a central nervous system depressant that increases gamma-aminobutyric acid (GABA) activity. Methaqualone toxicity data showed that it inhibits platelet aggregation, increases prothrombin time and partial thromboplastin time, and lowers factors V and VII, all of which can cause retinal, conjunctival, and gastrointestinal hemorrhage. In silico investigation showed that Methaqualone antagonises Vitamin K in the extrinsic and intrinsic pathways of blood clotting, which leads to an increase in prothrombin time and partial thromboplastin time and lowers factors V and VII. Further, a molecular modelling study proved that inhibition of the P2Y12R by Methaqualone is responsible for the inhibition of platelet aggregation. This study systematically correlates all Methaqualone's blood-related toxicity, which results in conjunctival, retinal, and gastrointestinal hemorrhage.

Rational design of novel pyridine-based drugs candidates for lymphoma therapy

Research efforts to develop an effective drug for lymphoma with minimal side effects are still very slow. To aid the discovery of new lymphoma drug, we led an extensive in silico computational study based on pharmacophore QSAR modeling, DFT, Molecular Docking, ADME-Tox, biophysical simulation approaches such as Molecular Dynamics analysis (MD) and comprehensive MM-GBSA free binding energy computations on a novel series of pyridine derivatives as promising MALT1 allosteric inhibitors (PDB code: 4I1R). The developed QSAR models demonstrated a strong correlation between the 2D/3D structural properties of pyridine derivatives and their biological inhibitory activity against MALT1 protease enzymatic activity. Based on detailed structural characterizations provided by the QSAR modeling, the biological inhibitory activity of four novel small molecules derived from the template molecule S40 (pIC50 = 8.00) was improved. Based on the molecular modeling and computer-aided drug design approaches used in this work, the lead novel compounds C2 (pIC50 > 8, BE = -9.4 kcal/mol, ΔGbind = -58.15 kcal/mol) and C3 (pIC50 > 8, BE = -8.7 kcal/mol, ΔGbind = -51.31 kcal/mol) were identified as optimal candidate allosteric inhibitors for MALT1 compared to the synthesized templates molecules S40 and Thioridazine. Finally, biophysical simulations demonstrated the high stability of the modeled ligands C2 and C3 inside the active pocket of the MALT1 protease in aqueous conditions throughout the 100 ns trajectory of the MD simulations. Thus, small designed hit compounds C2 and C3 can be used as valid references for design new drugs for lymphoma therapy by targeting MALT1 protease enzymatic activity.

Ab initio modelling of an essential mammalian protein: Transcription Termination Factor 1 (TTF1)

Transcription Termination Factor 1 (TTF1) is an essential mammalian protein that regulates transcription, replication fork arrest, DNA damage repair, chromatin remodelling etc. TTF1 interacts with numerous cellular proteins to regulate various cellular phenomena which play a crucial role in maintaining normal cellular physiology, and dysregulation of this protein has been reported to induce oncogenic transformation of the cells. However, despite its key role in many cellular processes, the complete structure of human TTF1 has not been elucidated to date, neither experimentally nor computationally. Therefore, understanding the structure of human TTF1 is crucial for studying its functions and interactions with other cellular factors. The aim of this study was to construct the complete structure of human TTF1 protein, using molecular modelling approaches. Owing to the lack of suitable homologues in the Protein Data Bank (PDB), the complete structure of human TTF1 was constructed by ab initio modelling. The structural stability was determined with molecular dynamics (MD) simulations in explicit solvent, and trajectory analyses. The frequently occurring conformation of human TTF1 was selected by trajectory clustering, and the central residues of this conformation were determined by centrality analyses of the Residue Interaction Network (RIN) of TTF1. Two residue clusters, one in the oligomerization domain and other in the C-terminal domain, were found to be central to the structural stability of human TTF1. To the best of our knowledge, this study is the first to report the complete structure of this essential mammalian protein, and the results obtained herein will provide structural insights for future research including that in cancer biology and related studies. Communicated by Ramaswamy H. Sarma

Comparing the difference in enhancement of kokumi-tasting γ-glutamyl peptides on basic taste via molecular modeling approaches and sensory evaluation

γ-Glutamyl peptides can enhance basic taste sensations such as saltiness, sweetness, and umaminess, while the molecular mechanism and the difference in taste enhancement remain elusive. Thus, two complex conformations: taste type 1 receptor 1 (T1R1)-MSG and taste type 1 receptor 2 (T1R2)-sucrose were constructed to form binding receptors. These peptides showed affinity for the two receptors, but a higher affinity scores and more binding amino acid residues for the T1R1-MSG receptor, implying that they may exhibit a higher umami-enhancing effect. Thereinto, γ-glutamyl alanine (γ-EA) displayed the highest affinity for the two receptors through mobilizing multiple amino acid residues to form hydrophobic and hydrogen bonds, indicating it had the highest enhancement for umaminess and sweetness among these peptides. Sensory evaluation demonstrated the enhancement of γ-EA on umaminess was superior to that of sweetness. Generally, γ-glutamyl peptides could enhance basic taste sensation via activating taste receptor, and exhibited a highest umami-enhancing effect.

A holistic molecular modelling approach to design novel indole-2-carboxamide derivatives as potential inhibitors of MmpL3

ABSTRACT Tuberculosis is an infectious air-borne disease and one of the leading causes of death globally among all infectious diseases. There is an urgent need to develop antitubercular drugs that would be highly efficient and less toxic than the presently available marketed drugs. Mycobacterium membrane protein large 3 (MmpL3) is an emerging drug target in tuberculosis with various classes of molecules that have been known to inhibit it. In this study, a dataset of indole-2-carboxamides showing antitubercular activity by inhibiting MmpL3 was utilized. Initially, a chimera-based homology model was developed and docking was performed with the filtered dataset to analyse the interactions. Thereafter, molecular dynamics simulations were run with representative molecules to gain a better insight on the binding patterns. To attain a more quantitative correlation, an atom-based 3D QSAR model was developed which complemented the results from the previous models. A library of novel indole-2-carboxamides was then generated using core hopping-based ligand enumeration and upon screening on our workflow model it predicted three molecules as potent antitubercular compounds. This work not only helps to gain new insights on the interactions at the MmpL3 binding site but also provides novel indole-2-carboxamides having the potential to become antitubercular drugs in future.

Prophylactic Anti-Osteoporotic Effect of Matricaria chamomilla L. Flower Using Steroid-Induced Osteoporosis in Rat Model and Molecular Modelling Approaches.

The anti-osteoporotic activity of ethanol extract from the Matricaria chamomilla L. flower was evaluated using steroid-induced osteoporosis in a rat model for the first time. Biochemical parameters such as serum calcium, phosphate, magnesium, creatinine, and alkaline phosphatase were assessed. At a 400 mg/kg body weight dose, the extract showed 54.01% and 27.73% reduction in serum calcium and phosphate ions serum levels, respectively. Meanwhile, it showed a 20% elevation in serum magnesium level, compared to the steroid-treated group. It also showed a significant decrease in creatinine and alkaline phosphatase levels, by 29.41% and 27.83%, respectively. The obtained results were further supported by biomechanical analyses, which revealed that a 400 mg/kg body weight dose of the flower extract increased bone strength and thickness. At the same time, it does not affect the bone length, compared to the diseased group. Histopathological examination revealed that the extract showed a significant increase in trabecular thickness, and it had restored the architecture of the cortical and trabecular structure with well-organized bone matrix. The possible inhibitory effect of the major phenolic compounds identified from the plant extract on cathepsin K was investigated using molecular docking. Rutin (4) had the best-fitting score within the active site, as evidenced by the free binding energy, (∆G = −54.19 Kcal/mol). ADMET/TOPKAT revealed that the examined compounds had variable pharmacodynamics and pharmacokinetic properties that could be improved to enhance the bioavailability during incorporation in various dosage forms. Thus, it can be concluded that this plant extract showed potential therapeutic benefits for osteoporosis.

Molecular Modeling Approaches Can Reveal the Molecular Interactions Established between a Biofilm and the Bioactive Compounds of the Essential Oil of Piper divaricatum.

Molecular modeling approaches are used in a versatile way to investigate the properties of diverse organic and inorganic structures such as proteins, biomolecules, nanomaterials, functionalized nanoparticles, and membranes. However, more detailed studies are needed to understand the molecular nature of interactions established in gelatin biofilms impregnated with bioactive compounds. Because of this, we used computational methods to evaluate how the major compounds of Piper divaricatum essential oil can interact with the gelatin biofilm structure. For this, we used as inspiration the paper published, where various properties of the essential oil impregnated gelatin biofilm P. divaricatum are reported. After our computer simulations, we related our molecular observations to biofilm’s structural and mechanical properties. Our results suggest that the major compounds of the essential oil were able to interrupt intermolecular interactions between the chains of the biofilm matrix. However, the compounds also established interactions with the amino acid residues of these chains. Our molecular analyses also explain changes in the structural and mechanical properties of the essential oil-impregnated biofilm. These results can support the planning of functional packaging impregnated with bioactive compounds that can protect food against microorganisms harmful to human health.

Adhesion and Cohesion of Silica Surfaces with Quartz Cement: A Molecular Simulations Study.

This study focuses on developing an adhesive and cohesive molecular modeling approach to study the properties of silica surfaces and quartz cement interfaces. Atomic models were created based on reported silica surface configurations and quartz cement. For the first time, molecular dynamics (MD) simulations were conducted to investigate the cohesion and adhesion properties by predicting the interaction energy and the adhesion pressure at the cement and silica surface interface. Results show that the adhesion pressure depends on the area density (per nm2) and degree of ionization, and van der Waals forces are the major contributor to the interactions between the cement and silica surfaces. Moreover, it is shown that adhesion pressure could be the actual rock failure mechanism in contrast to the reported literature which considers cohesion as the failure mechanism. The bonding energy factors for both “dry” and “wet” conditions were used to predict the water effect on the adhesion pressure at the cement–surface interface, revealing that H2O can cause a significant reduction in adhesion pressure. In addition, relating the adhesion pressure to the dimensionless area ratio of the cement to silica surfaces resulted in a good correlation that could be used to distribute the adhesion pressure in a rock system based on the area of interactions between the cement and the surface. This study shows that MD simulations can be used to understand the chemomechanics relationship fundamental of cement–surfaces of a reservoir rock at a molecular/atomic level and to predict the rock mechanical failure for sandstones, limestones, and shales.

Structural Dynamics of the SARS-CoV-2 Spike Protein: A 2-Year Retrospective Analysis of SARS-CoV-2 Variants (from Alpha to Omicron) Reveals an Early Divergence between Conserved and Variable Epitopes.

We analyzed the epitope evolution of the spike protein in 1,860,489 SARS-CoV-2 genomes. The structural dynamics of these epitopes was determined by molecular modeling approaches. The D614G mutation, selected in the first months of the pandemic, is still present in currently circulating SARS-CoV-2 strains. This mutation facilitates the conformational change leading to the demasking of the ACE2 binding domain. D614G also abrogated the binding of facilitating antibodies to a linear epitope common to SARS-CoV-1 and SARS-CoV-2. The main neutralizing epitope of the N-terminal domain (NTD) of the spike protein showed extensive structural variability in SARS-CoV-2 variants, especially Delta and Omicron. This epitope is located on the flat surface of the NTD, a large electropositive area which binds to electronegatively charged lipid rafts of host cells. A facilitating epitope located on the lower part of the NTD appeared to be highly conserved among most SARS-CoV-2 variants, which may represent a risk of antibody-dependent enhancement (ADE). Overall, this retrospective analysis revealed an early divergence between conserved (facilitating) and variable (neutralizing) epitopes of the spike protein. These data aid in the designing of new antiviral strategies that could help to control COVID-19 infection by mimicking neutralizing antibodies or by blocking facilitating antibodies.