Evaluation on performance of MM/PBSA in nucleic acid-protein systems

The molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) method has been widely used in predicting the binding affinity among ligands, proteins, and nucleic acids. However, the accuracy of the predicted binding energy by the standard MM/PBSA is not always good, especially in highly charged systems. In this work, we take the protein-nucleic acid complexes as an example, and showed that the use of screening electrostatic energy (instead of Coulomb electrostatic energy) in molecular mechanics can greatly improve the performance of MM/PBSA. In particular, the Pearson correlation coefficient of dataset II in the modified MM/PBSA (i.e., screening MM/PBSA) is about 0.52, much better than that (< 0.33) in the standard MM/PBSA. Further, we also evaluate the effect of solute dielectric constant and salt concentration on the performance of the screening MM/PBSA. The present study highlights the potential power of the screening MM/PBSA for predicting the binding energy in highly charged bio-systems.     

Solvent effects and potential of mean force study of the S_N2 reaction of CH_3F+CN~- in water

We used a combined quantum mechanics and molecular mechanics(QM/MM) method to investigate the solvent effects and potential of mean force of the CH_3F+CN~- reaction in water. Comparing to gas phase, the water solution substantially affects the structures of the stationary points along the reaction path. We quantitatively obtained the solvent effects' contributions to the reaction: 1.7 kcal/mol to the activation barrier and -26.0 kcal/mol to the reaction free energy.The potential mean of force calculated with the density functional theory/MM theory has a barrier height at 19.7 kcal/mol,consistent with the experimental result at 23.0 kcal/mol; the calculated reaction free energy at -43.5 kcal/mol is also consistent with the one estimated based on the gas-phase data at -39.7 kcal/mol.     

极化蛋白专一性电荷在HIV-1蛋白酶-抑制剂结合自由能预测中的应用

对人类免疫缺陷病毒（HIV-1）蛋白酶-抑制剂复合物分别在AMBER力场及极化专一性蛋白电荷（PPC）下进行10 ns的分子动力学模拟（MD）,并用MM/PBSA方法计算结合自由能.PPC是基于线性标度的量子力学计算的静电势拟合的蛋白质电荷,能够更准确地描述蛋白质所处的静电环境.结果表明：PPC电荷计算的结合自由能比AMBER力场计算的结合自由能更接近实验值.     

Combined multi-level quantum mechanics theories and molecular mechanics study of water-induced transition state of OH~- + CO_2 reaction in aqueous solution

The presence of a solvent interacting with a system brings about qualitative changes from the corresponding gasphase reactions. A solvent can not only change the energetics along the reaction pathway, but also radically alter the reaction mechanism. Here, we investigated the water-induced transition state of the OH~- + CO_2→ HCO_3~- reaction using a multi-level quantum mechanics and molecular mechanics method with an explicit water model. The solvent energy contribution along the reaction pathway has a maximum value which induces the highest energy point on the potential of mean force. The charge transfer from OH~- to CO_2 results in the breaking of the OH~- solvation shell and the forming of the CO_2 solvation shell. The loss of hydrogen bonds in the OH~-solvation shell without being compensated by the formation of hydrogen bonds in the CO_2 solvation shell induces the transition state in the aqueous solution. The calculated free energy reaction barrier at the CCSD(T)/MM level of theory, 11.8 kcal/mol, agrees very well with the experimental value, 12.1 kcal/mol.     

Structure-based virtual screening,in silico docking,ADME properties prediction and molecular dynamics studies for the identification of potential inhibitors against SARS-CoV-2 Mpro

COVID-19 is a viral pandemic caused by SARS-CoV-2. Due to its highly contagious nature, millions of people are getting affected worldwide knocking down the delicate global socio-economic equilibrium. According to the World Health Organization, COVID-19 has affected over 186 million people with a mortality of around 4 million as of July 09, 2021. Currently, there are few therapeutic options available for COVID-19 control. The rapid mutations in SARS-CoV-2 genome and development of new virulent strains with increased infection and mortality among COVID-19 patients, there is a great need to discover more potential drugs for SARS-CoV-2 on a priority basis. One of the key viral enzymes responsible for the replication and maturation of SARS-CoV-2 is M^pro protein. In the current study, structure-based virtual screening was used to identify four potential ligands against SARS-CoV-2 M^pro from a set of 8,722 ASINEX library compounds. These four compounds were evaluated using ADME filter to check their ADME profile and druggability, and all the four compounds were found to be within the current pharmacological acceptable range. They were individually docked to SARS-CoV-2 M^pro protein to assess their molecular interactions. Further, molecular dynamics (MD) simulations was carried out on protein–ligand complex using Desmond at 100 ns to explore their binding conformational stability. Based on RMSD, RMSF and hydrogen bond interactions, it was found that the stability of protein–ligand complex was maintained throughout the entire 100 ns simulations for all the four compounds. Some of the key ligand amino acid residues participated in stabilizing the protein–ligand interactions includes GLN 189, SER 10, GLU 166, ASN 142 with PHE 66 and TRP 132 of SARS-CoV-2 M^pro. Further optimization of these compounds could lead to promising drug candidates for SARS-CoV-2 M^pro target.

     

Fe2O3上AsH3催化氧化反应机理的理论研究

本文采用密度泛函理论方法研究了Fe₂O₃上AsH₃的催化氧化反应机理.该反应以Fe₂O₃中的两个Fe原子为不同的活性中心进行研究,每个活性中心均设计了3个步骤. AsH₃分子依次与3个O₂分子在催化剂上相互作用分别形成中间体H₃AsO₂、H₃AsO₄及最终产物H₃AsO₆.研究发现,当氧化反应发生在1号铁原子(Fe1)附近,其速度控制步骤活化自由能垒为49.99 kcal/mol;当氧化反应发生在2号铁原子(Fe2)附近,其活化自由能垒为21.20 kcal/mol,与直接氧化(50.14 kcal/mol)相比大大降低.可见AsH₃在Fe₂O₃上的催化氧化反应更易发生在Fe2附近.     

基于参考势的从头算量子力学/分子力学混合方法研究Parvalbumin B蛋白结合钙、镁离子的选择性

蛋白的离子选择性与蛋白的功能密切相关,而离子选择性本质上来源于蛋白分子与离子结合自由能的差别. 尽管近几十年来分子力场在描述蛋白体系相互作用方面取得了长足的进步,由于缺乏对静电极化和电荷转移效应显式的描述,传统的分子力场依然难以精确地描述金属蛋白体系中蛋白质与金属离子的相互作用. 量子化学方法非常适合于蛋白质与金属离子之间相互作用的描述. 但是在分子模拟中采用量子化学方法则太昂贵了. 近年来发展起来的参考势方法在保证计算精度的前提下兼顾效率,可以有效地解决这个窘境. 在这个方法中,动力学模拟的轨迹是在分子力场的精度下获得的. 随后,通过从分子力场到量子化学方法的矫正,从而获得在量子化学势函数级别下的自由能信息. 本文采用参考势函数方法研究了Parvalbumin B蛋白的结合口袋对钙、镁离子的选择性. 计算结果表明电荷转移效应非常重要,而量子化学方法可以比较精确地预测离子的选择性. 并且,量子化学区域的选择对于结果的可靠性也是非常重要的.     

Entropy and Free Energy of a Mobile Loop Based on the Crystal Structures of the Free and Bound Proteins

A mobile loop changes its conformation from "open" (free enzyme) to "closed" upon ligand binding. The difference in the Helmholtz free energy, ΔF(loop) between these states sheds light on the mechanism of binding. With our "hypothetical scanning molecular dynamics" (HSMD-TI) method ΔF(loop) = F(free) - F(bound) where F(free) and F(bound) are calculated from two MD samples of the free and bound loop states; the contribution of water is obtained by a thermodynamic integration (TI) procedure. In previous work the free and bound loop structures were both attached to the same "template" which was "cut" from the crystal structure of the free protein. Our results for loop 287-290 of AcetylCholineEsterase agree with the experiment, ΔF(loop)~ -4 kcal/mol if the density of the TIP3P water molecules capping the loop is close to that of bulk water, i.e., N(water) = 140 - 180 waters in a sphere of a 18 ? radius. Here we calculate ΔF(loop) for the more realistic case, where two templates are "cut" from the crystal structures, 2dfp.pdb (bound) and 2ace.pdb (free), where N(water) = 40 - 160; this requires adding a computationally more demanding (second) TI procedure. While the results for N(water) ≤ 140 are computationally sound, ΔF(loop) is always positive (18 ± 2 kcal/mol for N(water) = 140). These (disagreeing) results are attributed to the large average B-factor, 41.6 of 2dfp (23.4 ?(2) for 2ace). While this conformational uncertainty is an inherent difficulty, the (unstable) results for N(water) = 160 suggest that it might be alleviated by applying different (initial) structural optimizations to each template.     

Structural and electronic effects in acetone adsorption over TiO<Subscript>2</Subscript> anatase clusters as the first stage of photocatalytic oxidation

Photocatalytic oxidation is used for air purification from low concentrations of organic compounds and microbiological objects. Adsorption is the first stage of photocatalytic oxidation, and adsorption constant value has direct linear influence onto the rate of oxidation at low concentration according to the Langmuir-Hinshelwood equation. The present computational investigation has been undertaken with the goal to estimate the effect of nanoparticle size in the range of 1–1.5 nm, extent of hydroxylation, surface acidity, and nanoparticle shape on adsorption of acetone over TiO₂ anatase particle facets, edges, and vertices. The anatase nanoparticles were represented by three cluster models—two of cubic shape and one of decahedral shape with exposed surfaces (001), (100), and (101). Adsorption energy was calculated with density functional tight binding (DFTB) semiempirical method and varied from ? 0.67 to ? 25.79 kcal/mol for different sites of the clusters depending on facet types and location on a facet. Mean unweighted adsorption energy of acetone increased from ? 4.49 to ? 8.16 kcal/mol for (001) facet and from ? 11.05 to ? 12.97 kcal/mol for (100) facet when the cubic cluster size increased from 3 × 3 × 1 to 4 × 4 × 1 elementary cells. For decahedral cluster, mean adsorption energy on (001) facet was ? 9.87 kcal/mol and ? 14.44 kcal/mol on (101) facets. The largest adsorption energy ? 25.60 and ? 25.79 kcal/mol was observed on grove Ti atoms on (100) facet of the largest cubic cluster and vertex atoms in decahedral cluster, respectively. Dissociative adsorption of one and two water molecules on (001) facet increased acetone adsorption energy from ? 4.02 to ? 8.20 and to ? 18.50 kcal/mol. A marked electronic effect on adsorption energy was observed for two adjacent sites on (001) facet with a similar structure but adsorption energy ? 16.40 and ? 1.40 kcal/mol. Influence of acetone adsorption on clusters’ band gap, photogenerated thermalized electron and hole location, and C=O vibration wavenumber is also reported.     

QM/MM study of hydrolysis of arginine catalysed by arginase

ABSTRACT

In this paper, we have investigated the catalytic mechanism of rat liver arginase using a quantum mechanics/molecular mechanics (QM/MM) approach. The enzyme catalyses the hydrolysis of L-arginine (L-Arg) to generate L-ornithine and urea. The reaction mechanism proposed by the previous experimental studies is well reproduced by the QM/MM computations. The explicit treatment of the protein environment suggests that Glu277 fulfil its role in stabilising and orienting L-Arg before nucleophilic attack by the bridging hydroxide in the first step. We have also found that the proton transfer step involving a hydrogen bond switch is the rate-limiting step. The activation energy is computed to be 9.0 and 5.9 kcal/mol at the UB3LYP-D3/CHARMM22 and UBHandHLYP-D3/CHARMM22 levels, which are comparable to the observed activation barrier of 7.2 kcal/mol.     

A new glimpse on the active site of SARS-CoV-2 3CLpro,coupled with drug repurposing study

Molecular Diversity - Coronavirus disease 2019 (COVID-19) is caused by novel severe acute respiratory syndrome coronavirus (SARS-CoV-2). Its main protease, 3C-like protease (3CLpro), is an...     

Cr/Ti掺杂石墨烯活化CO2分解的理论研究

为筛选更高效的CO2分解还原的催化材料,采用密度泛函理论中的B3LYP方法结合6-31G(d)基组,研究了Cr、Ti掺杂石墨烯对CO2分子的吸附与催化分解的机理.研究结果表明：CO2分子在Cr元素和Ti元素掺杂石墨烯表面的吸附为放热过程,吸附能分别为28.3kcal/mol和7.7kcal/mol,两种元素掺杂石墨烯催化CO2分子中C-O断裂的活化能分别为15.5kcal/mol和7.8kcal/mol,反应过程遵循插入-消除原理,计算结果为CO2还原的催化剂设计提供理论指导.     

On the nature of the SO4/Ag(111) and SO4/Au(111) surface bonding

The nature of sulfate-Ag(111) and sulfate-Au(111) surface bonding has been investigated at the SCF + MP2 level of theory. Convergence of binding energy with cluster size is investigated and, unlike neutral adsorbates, large clusters are required in order to obtain reliable binding energies. In the most stable adsorption mode, sulfate binds to the surface via three oxygen atoms (C_3v symmetry) with a binding energy of 159.3 kcal/mol on Ag(111) and 143.9 kcal/mol on Au(111). The geometry of adsorbed sulfate was optimized at the SCF level. While the bond length between sulfur and the oxygens coordinated to the surface increases, the sulfur-uncoordinated oxygen bond length decreases. This weakening and strengthening of the bonds, respectively, is consistent with bond order conservation in adsorbates on metal surfaces. Although a charge transfer of 0.4 electrons towards the metal is observed, the adsorbate remains very much sulfate-like. The molecular orbital analysis indicates that there is also some charge back-donation towards unoccupied orbitals of sulfate. This results in an increased electron density around sulfur as revealed in the electron density difference maps. Analysis of the Laplacian of the charge density of free sulfate provides a suitable framework to understand the nature of the different charge transfer processes and allows us to establish some similarities with the CO- and SO₂-metal bondings.     

基于深度学习的冠状病毒刺突蛋白拉曼特征峰的理论研究

持续一年的新冠疫情对全球的经济造成了巨大破坏,为了有效控制新冠疫情,快速检测新冠病毒(SARS-CoV-2)是一个急需解决的问题。新冠病毒的刺突蛋白（spikeprotein）是拉曼光谱技术检测新冠病毒的检测点,构建刺突蛋白拉曼特征峰模型对于发展拉曼检测技术快速检测新冠病毒具有重要作用。基于简化的激子模型,利用深度神经网络技术,构建了刺突蛋白的酰胺Ⅰ、Ⅲ特征峰模型,并结合已知可以感染人类的七种冠状病毒（HCoV-229E,HCoV-HKU1,HCoV-NL63,HCoV-OC43,MERS-CoV,SARS-CoV和SARS-CoV-2）刺突蛋白的实验结构,分析了七种冠状病毒刺突蛋白酰胺Ⅰ、Ⅲ特征峰的区别。计算结果表明,七种冠状病毒可以根据毒刺突蛋白的酰胺Ⅰ、Ⅲ特征峰划分为四个组：SARS-CoV-2,SARS-CoV,MERS-CoV形成一个组;HCoV-HKU1,HCoV-NL63形成一个组;HCoV-229E和HCoV-OC43各自独立形成一个组。相同组的冠状病毒刺突蛋白酰胺Ⅰ、Ⅲ峰频率较为接近,通过酰胺Ⅰ、Ⅲ峰的频率较难区分刺突蛋白;不同组的冠状病毒刺突蛋白酰胺Ⅰ、Ⅲ特征峰差异较大,刺突蛋白可以通过拉曼技术区分开来。该结果为发展拉曼检测技术快速检测新冠病毒提供了定性判断的理论依据。     

Identification of phytocompounds from Houttuynia cordata Thunb. as potential inhibitors for SARS-CoV-2 replication proteins through GC–MS/LC–MS characterization,molecular docking and molecular dynamics simulation

The COVID-19 pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a massive viral disease outbreak of international concerns. The present study is mainly intended to identify the bioactive phytocompounds from traditional antiviral herb Houttuynia cordata Thunb. as potential inhibitors for three main replication proteins of SARS-CoV-2, namely Main protease (Mpro), Papain-Like protease (PLpro) and ADP ribose phosphatase (ADRP) which control the replication process. A total of 177 phytocompounds were characterized from H. cordata using GC–MS/LC–MS and they were docked against three SARS-CoV-2 proteins (receptors), namely Mpro, PLpro and ADRP using Epic, LigPrep and Glide module of Schrödinger suite 2020-3. During docking studies, phytocompounds (ligand) 6-Hydroxyondansetron (A104) have demonstrated strong binding affinity toward receptors Mpro (PDB ID 6LU7) and PLpro (PDB ID 7JRN) with G-score of???7.274 and???5.672, respectively, while Quercitrin (A166) also showed strong binding affinity toward ADRP (PDB ID 6W02) with G-score -6.788. Molecular Dynamics Simulation (MDS) performed using Desmond module of Schrödinger suite 2020–3 has demonstrated better stability in the ligand–receptor complexes A104-6LU7 and A166-6W02 within 100 ns than the A104-7JRN complex. The ADME-Tox study performed using SwissADMEserver for pharmacokinetics of the selected phytocompounds 6-Hydroxyondansetron (A104) and Quercitrin (A166) demonstrated that 6-Hydroxyondansetron passes all the required drug discovery rules which can potentially inhibit Mpro and PLpro of SARS-CoV-2 without causing toxicity while Quercitrin demonstrated less drug-like properties but also demonstrated as potential inhibitor for ADRP. Present findings confer opportunities for 6-Hydroxyondansetron and Quercitrin to be developed as new therapeutic drug against COVID-19.

Graphic abstract

     

Computational investigation of drug bank compounds against 3C-like protease (3CLpro) of SARS-CoV-2 using deep learning and molecular dynamics simulation

Blocking the main replicating enzyme, 3 Chymotrypsin-like protease (3CL^pro) is the most promising drug development strategy against the SARS-CoV-2 virus, responsible for the current COVID-19 pandemic. In the present work, 9101 drugs obtained from the drug bank database were screened against SARS-CoV-2 3CL^pro prosing deep learning, molecular docking, and molecular dynamics simulation techniques. In the initial stage, 500 drug-screened by deep learning regression model and subjected to molecular docking that resulted in 10 screened compounds with strong binding affinity. Further, five compounds were checked for their binding potential by analyzing molecular dynamics simulation for 100 ns at 300 K. In the final stage, two compounds {4-[(2s,4e)-2-(1,3-Benzothiazol-2-Yl)-2-(1h-1,2,3-Benzotriazol-1-Yl)-5-Phenylpent-4-Enyl]Phenyl}(Difluoro)Methylphosphonic Acid and 1-(3-(2,4-dimethylthiazol-5-yl)-4-oxo-2,4-dihydroindeno[1,2-c]pyrazol-5-yl)-3-(4-methylpiperazin-1-yl)urea were screened as potential hits by analyzing several parameters like RMSD, Rg, RMSF, MMPBSA, and SASA. Thus, our study suggests two potential drugs that can be tested in the experimental conditions to evaluate the efficacy against SARS-CoV-2. Further, such drugs could be modified to develop more potent drugs against COVID-19.

Graphic abstract

     

Multi-scale mechanism of antiviral drug-alike phytoligands from Ayurveda in managing COVID-19 and associated metabolic comorbidities: insights from network pharmacology

The novel coronavirus disease (COVID-19), which emerged in Wuhan, China, is continuously spreading worldwide, creating a huge burden on public health and economy. Ayurveda, the oldest healing schema of Traditional Indian Medicinal (TIM) system, is considered as a promising CAM therapy to combat various diseases/ disorders. To explore the regulatory mechanisms of 3038 Ayurvedic herbs (AHs) against SARS-CoV-2, in this study, multi-targeting and synergistic actions of constituent 34,472 phytochemicals (APCs) are investigated using a comprehensive approach comprising of network pharmacology and molecular docking. Immunomodulatory prospects of antiviral drug-alike potentially effective phytochemicals (PEPs) are presented as a special case study, highlighting the importance of 6 AHs in eliciting the antiviral immunity. By evaluating binding affinity of 292 PEPs against 24 SARS-CoV-2 proteins, we develop and analyze a high-confidence “bi-regulatory network” of 115 PEPs having ability to regulate protein targets in both virus and its host human system. Furthermore, mechanistic actions of PEPs against cardiovascular complications, diabetes mellitus and hypertension are also investigated to address the regulatory potential of AHs in dealing with COVID-19-associated metabolic comorbidities. The study further reports 12 PEPs as promising source of COVID-19 comorbidity regulators.

Graphical abstract

     

Microwave spectrum of (CH3)3CCN-SO3

Eight rotational transitions of the complex (CH₃)₃CCN-SO₃ have been recorded using pulsed-nozzle Fourier transform microwave spectroscopy and a series of ab initio calculations has been performed. The complex is a symmetric top with free or nearly free internal rotation of the SO₃ and (CH₃)₃CCN subunits. The nitrogen-sulfur bond distance is determined to be 2.394(19) Å. Calculations at the MP2/aug-cc-pVTZ level/basis, which are in excellent agreement with the experimental results, give a binding energy of 11.0 kcal/mol relative to (CH₃)₃CCN and SO₃. Physical properties of the system, including N-S bond length, N-S-O angle, binding energy, and the degree of electron transfer (obtained from Townes and Dailey analysis of the ¹⁴N nuclear quadrupole coupling constant) are compared with those of similar complexes. The proton affinity of the base is a useful parameter for ordering complexes in the series.     

New insights into the catalytic mechanism of the SARS-CoV-2 main protease: an ONIOM QM/MM approach

Molecular Diversity - SARS-CoV-2 Mpro, also known as the main protease or 3C-like protease, is a key enzyme involved in the replication process of the virus that is causing the COVID-19 pandemic....     

Conformational analysis of 3,3‐dimethyl‐3‐silathiane, 2,3,3‐trimethyl‐3‐silathiane and 2‐trimethylsilyl‐3,3‐dimethyl‐3‐silathiane—preferred conformers,barriers to ring inversion and substituent effects

The first conformational analysis of 3‐silathiane and its C‐substituted derivatives, namely, 3,3‐dimethyl‐3‐silathiane 1 , 2,3,3‐trimethyl‐3‐silathiane 2 , and 2‐trimethylsilyl‐3,3‐dimethyl‐3‐silathiane 3 was performed by using dynamic NMR spectroscopy and B3LYP/6‐311G(d,p) quantum chemical calculations. From coalescence temperatures, ring inversion barriers ΔG^≠ for 1 and 2 were estimated to be 6.3 and 6.8 kcal/mol, respectively. These values are considerably lower than that of thiacyclohexane (9.4 kcal/mol) but slightly higher than the one of 1,1‐dimethylsilacyclohexane (5.5 kcal/mol). The conformational free energy for the methyl group in 2 (?ΔG° = 0.35 kcal/mol) derived from low‐temperature ¹³C NMR data is fairly consistent with the calculated value. For compound 2 , theoretical calculations give ΔE value close to zero for the equilibrium between the 2 ‐Me_ax and 2 ‐Me_eq conformers. The calculated equatorial preference of the trimethylsilyl group in 3 is much more pronounced (?ΔG° = 1.8 kcal/mol) and the predominance of the 3 ‐SiMe_{3 eq} conformer at room temperature was confirmed by the simulated ¹H NMR and 2D NOESY spectra. The effect of the 2‐substituent on the structural parameters of 2 and 3 is discussed. Copyright © 2010 John Wiley & Sons, Ltd.