Correction: Rapid prediction of possible inhibitors for SARS-CoV-2 main protease using docking and FPL simulations.

[This corrects the article DOI: 10.1039/D0RA06212J.].

Distal Hydrophobic Loop Modulates the Copper Active Site and Reaction of AA13 Polysaccharide Monooxygenases.

Polysaccharide monooxygenases (PMOs) use a type-2 copper center to activate O2 for the selective hydroxylation of one of the two C-H bonds of glycosidic linkages. Our electron paramagnetic resonance (EPR) analysis and molecular dynamics (MD) simulations suggest the unprecedented dynamic roles of the loop containing the residue G89 (G89 loop) on the active site structure and reaction cycle of starch-active PMOs (AA13 PMOs). In the Cu(II) state, the G89 loop could switch between an "open" and "closed" conformation, which is associated with the binding and dissociation of an aqueous ligand in the distal site, respectively. The conformation of the G89 loop influences the positioning of the copper center on the preferred substrate of AA13 PMOs. The dissociation of the distal ligand results in the bending of the T-shaped core of the Cu(II) active site, which could help facilitate its reduction to the active Cu(I) state. In the Cu(I) state, the G89 loop is in the "closed" conformation with a confined copper center, which could allow for efficient O2 binding. In addition, the G89 loop remains in the "closed" conformation in the Cu(II)-superoxo intermediate, which could prevent off-pathway superoxide release via exchange with the distal aqueous ligand. Finally, at the end of the reaction cycle, aqueous ligand binding to the distal site could switch the G89 loop to the "open" conformation and facilitate product release.

Flexible and high-sensitivity sensor based on Ti3C2-MoS2 MXene composite for the detection of toxic gases.

It is vital to have high sensitivity in gas sensors to allow the exact detection of dangerous gases in the air and at room temperature. In this study, we used 2D MXenes and MoS2 materials to create a Ti3C2-MoS2 composite with high metallic conductivity and a wholly functionalized surface for a significant signal. At room temperature, the Ti3C2-MoS2 composite demonstrated clear signals, cyclic response curves to NO2 gas, and gas concentration-dependent. The sensitivities of the standard Ti3C2-MoS2 (TM_2) composite (20 wt% MoS2) rose dramatically to 35.8%, 63.4%, and 72.5% when increasing NO2 concentrations to 10 ppm, 50 ppm, and 100 ppm, respectively. In addition, the composite showed reaction signals to additional hazardous gases, such as ammonia and methane. Our findings suggest that highly functionalized metallic sensing channels could be used to construct multigas-detecting sensors that are very sensitive in air and at room temperature.

Marine derivatives prevent wMUS81 in silico studies.

The winged-helix domain of the methyl methanesulfonate and ultraviolet-sensitive 81 (wMUS81) is a potential cancer drug target. In this context, marine fungi compounds were indicated to be able to prevent wMUS81 structure via atomistic simulations. Eight compounds such as D197 (Tryptoquivaline U), D220 (Epiremisporine B), D67 (Aspergiolide A), D153 (Preussomerin G), D547 (12,13-dihydroxyfumitremorgin C), D152 (Preussomerin K), D20 (Marinopyrrole B) and D559 (Fumuquinazoline K) were indicated that they are able to prevent the conformation of wMUS81 via forming a strong binding affinity to the enzyme via perturbation approach. The electrostatic interaction is the dominant factor in the binding process of ligands to wMUS81. The residues Trp55, Arg59, Leu62, His63 and Arg69 were found to frequently form non-bonded contacts and hydrogen bonds to inhibitors. Moreover, the influence of the ligand D197, which formed the lowest binding free energy to wMUS81, on the structural change of enzyme was investigated using replica exchange molecular dynamics simulations. The obtained results indicated that D197, which forms a strong binding affinity, can modify the structure of wMUS81. Overall, the marine compounds probably inhibit wMUS81 due to forming a strong binding affinity to the enzyme as well as altering the enzymic conformation.

Rapid prediction of possible inhibitors for SARS-CoV-2 main protease using docking and FPL simulations.

Originating for the first time in Wuhan, China, the outbreak of SARS-CoV-2 has caused a serious global health issue. An effective treatment for SARS-CoV-2 is still unavailable. Therefore, in this study, we have tried to predict a list of potential inhibitors for SARS-CoV-2 main protease (Mpro) using a combination of molecular docking and fast pulling of ligand (FPL) simulations. The approaches were initially validated over a set of eleven available inhibitors. Both Autodock Vina and FPL calculations produced consistent results with the experiments with correlation coefficients of R Dock = 0.72 ± 0.14 and R W = -0.76 ± 0.10, respectively. The combined approaches were then utilized to predict possible inhibitors that were selected from a ZINC15 sub-database for SARS-CoV-2 Mpro. Twenty compounds were suggested to be able to bind well to SARS-CoV-2 Mpro. Among them, five top-leads are periandrin V, penimocycline, cis-p-Coumaroylcorosolic acid, glycyrrhizin, and uralsaponin B. The obtained results could probably lead to enhance the COVID-19 therapy.

Oversampling Free Energy Perturbation Simulation in Determination of the Ligand-Binding Free Energy.

Determination of the ligand-binding affinity is an extremely interesting problem. Normally, the free energy perturbation (FEP) method provides an appropriate result. However, it is of great interest to improve the accuracy and precision of this method. In this context, temperature replica exchange molecular dynamics implementation of the FEP computational approach, which we call replica exchange free energy perturbation (REP) was proposed. In particular, during REP simulations, the system can easily escape from being trapped in local minima by exchanging configurations with high temperatures, resulting in significant improvement in the accuracy and precision of protein-ligand binding affinity calculations. The distribution of the decoupling free energy was enlarged, and its mean values were decreased. This results in changes in the magnitude of the calculated binding free energies as well as in alteration in the binding mechanism. Moreover, the REP correlation coefficient with respect to experiment ( RREP = 0.85 ± 0.15) is significantly boosted in comparison with the FEP one ( RFEP = 0.64 ± 0.30). Furthermore, the root-mean-square error (RMSE) of REP is also smaller than FEP, RMSEREP = 4.28 ± 0.69 versus RMSEFEP = 5.80 ± 1.11 kcal/mol, respectively. © 2019 Wiley Periodicals, Inc.

Prediction of AChE-ligand affinity using the umbrella sampling simulation.

Acetylcholinesterase (AChE) is characterized as a key target for designing inhibitors to prevent Alzheimer's disease (AD). The binding free energy of a ligand to the AChE enzyme is a critical factor to screen the potential inhibitor in addition to pharmacokinetics and pharmacology estimation. The biased sampling or umbrella sampling (US) method emerges as a reliable technique to estimate the AChE-inhibitor affinity. The affinity is computed as the difference between the largest and smallest values of the free energy change, obtained by using a potential of mean force (PMF) analysis. The obtained affinities overestimate the experimental ones with a value of ∼4.10 kcal/mol. However, a very good correlation coefficient (R=0.94) between the computational and experimental values is observed. Consequently, the obtained precision is high since the mean error of the free energy value is of δ=1.17 kcal/mol. The binding affinity of a new ligand can be consistently appraised via the US technique. Therefore, the absolute binding free energy of a ligand to the AChE protein can be obtained via the linear regression with the root-mean-square errors (RMSE) of 0.98 kcal/mol. The small value of RMSE implies that ligands revealing the similar binding affinities are able to be discriminated through the US simulations. In addition, the derivatives of Cordyceps were recently reported that they are able to inhibit the AChE enzyme, resulting in an improvement in learning and cognitive ability for curing AD. The active metabolites of Cordyceps were thus evaluated as the potential inhibitors for the AChE enzyme, and the 5-Carboxy-2'-deoxyuridine compound can inhibit the activity of the AChE enzyme. These compounds are also passed the testing of Lipinski's rule of five, toxicity, crossing blood-brain barrier (BBB) ability, and human intestinal absorption.

Effective Estimation of Ligand-Binding Affinity Using Biased Sampling Method.

The binding between two biomolecules is one of the most critical factors controlling many bioprocesses. Therefore, it is of great interest to derive a reliable method to calculate the free binding energy between two biomolecules. In this work, we have demonstrated that the binding affinity of ligands to proteins can be determined through biased sampling simulations. The umbrella sampling (US) method was applied on 20 protein-ligand complexes, including the cathepsin K (CTSK), type II dehydroquinase (DHQase), heat shock protein 90 (HSP90), and factor Xa (FXa) systems. The ligand-binding affinity was evaluated as the difference between the largest and smallest values of the free-energy curve, which was obtained via a potential of mean force analysis. The calculated affinities differ sizably from the previously reported experimental values, with an average difference of ∼3.14 kcal/mol. However, the calculated results are in good correlation with the experimental data, with correlation coefficients of 0.76, 0.87, 0.96, and 0.97 for CTSK, DHQase, HSP90, and FXa, respectively. Thus, the binding free energy of a new ligand can be reliably estimated using our US approach. Furthermore, the root-mean-square errors (RMSEs) of binding affinity of these systems are 1.13, 0.90, 0.37, and 0.25 kcal/mol, for CTSK, DHQase, HSP90, and FXa, respectively. The small RMSE values indicate the good precision of the biased sampling method that can distinguish the ligands exhibiting similar binding affinities.

Structural and Energetic Impact of Non-natural 7-Deaza-8-azaguanine, 7-Deaza-8-azaisoguanine, and Their 7-Substituted Derivatives on Hydrogen-Bond Pairing with Cytosine and Isocytosine.

The impact of 7-deaza-8-azaguanine (DAG) and 7-deaza-8-azaisoguanine (DAiG) modifications on the geometry and stability of the G:C Watson-Crick (cWW) base pair and the G:iC and iG:C reverse Watson-Crick (tWW) base pairs has been characterized theoretically. In addition, the effect on the same base pairs of seven C7-substituted DAG and DAiG derivatives, some of which have been previously experimentally characterized, has been investigated. Calculations indicate that all of these modifications have a negligible impact on the geometry of the above base pairs, and that modification of the heterocycle skeleton has a small impact on the base-pair interaction energies. Instead, base-pair interaction energies are dependent on the nature of the C7 substituent. For the 7-substituted DAG-C cWW systems, a linear correlation between the base-pair interaction energy and the Hammett constant of the 7-substituent is found, with higher interaction energies corresponding to more electron-withdrawing substituents. Therefore, the explored modifications are expected to be accommodated in both parallel and antiparallel nucleic acid duplexes without perturbing their geometry, while the strength of a base pair (and duplex) featuring a DAG modification can, in principle, be tuned by incorporating different substituents at the C7 position.

Atomistic investigation of an Iowa Amyloid-ß trimer in aqueous solution.

The self-assembly of Amyloid beta (Aß) peptides are widely accepted to associate with Alzheimer's disease (AD) via several proposed mechanisms. Because Aß oligomers exist in a complicated environment consisting of various forms of Aß, including oligomers, protofibrils, and fibrils, their structure has not been well understood. The negatively charged residue D23 is one of the critical residues of the Aß peptide as it is located in the central hydrophobic domain of the Aß N-terminal and forms a salt-bridge D23-K28, which helps stabilize the loop domain. In the familial Iowa (D23N) mutant, the total net charge of Aß oligomers decreases, resulting in the decrease of electrostatic repulsion between D23N Aß monomers and thus the increase in their self-aggregation rate. In this work, the impact of the D23N mutation on 3Aß11-40 trimer was characterized utilizing temperature replica exchange molecular dynamics (REMD) simulations. Our simulation reveals that D23N mutation significantly enhances the affinity between the constituting chains in the trimer, increases the ß-content (especially in the sequence 21-23), and shifts the ß-strand hydrophobic core from crossing arrangement to parallel arrangement, which is consistent with the increase in self-aggregation rate. Molecular docking indicates that the Aß fibril-binding ligands bind to the D23N and WT forms at different poses. These compounds prefer to bind to the N-terminal ß-strand of the D23N mutant trimer, while they mostly bind to the N-terminal loop region of the WT. It is important to take into account the difference in the binding of ligands to mutant and wild type Aß peptides in designing efficient inhibitors for various types of AD.

Palladium N-Heterocyclic Carbene Precatalyst Site Isolated in the Core of a Star Polymer.

An approach for supporting a Pd-NHC complex on a soluble star polymer with nanoscale dimensions is described. The resulting star polymer catalyst exhibits excellent activity in cross-coupling reactions, is stable in air and moisture, and is easily recoverable and recyclable. These properties are distinct and unattainable with the small-molecule version of the same catalyst.

One-pot synthesis of Au@SiO(2) catalysts: a click chemistry approach.

Using the copper-catalyzed azide-alkyne cycloaddition "click" reaction, a library of triazole amphiphiles with a variety of functional polar "heads" and hydrophobic or superhydrophobic "tails" was synthesized. The amphiphiles were evaluated for their ability to stabilize small Au nanoparticles, and, at the same time, serve as templates for nanocasting porous SiO2. One of the Au@SiO2 materials thus prepared was found to be a highly active catalyst for the Au nanoparticle-catalyzed regioselective hydroamination of alkynes.