Computational Characterization of Nanosystems

Nanosystems play an important role in many applications. Due to their complexity, it is challenging to accurately characterize their structure and properties. An important means to reach such a goal is computational simulation, which is grounded on ab initio electronic structure calculations. Low scaling and accurate electronic-structure algorithms have been developed in recent years. Especially, the efficiency of hybrid density functional calculations for periodic systems has been significantly improved. With electronic structure information, simulation methods can be developed to directly obtain experimentally comparable data. For example, scanning tunneling microscopy images can be effectively simulated with advanced algorithms. When the system we are interested in is strongly coupled to environment, such as the Kondo effect, solving the hierarchical equations of motion turns out to be an effective way of computational characterization. Furthermore, the first principles simulation on the excited state dynamics rapidly emerges in recent years, and nonadiabatic molecular dynamics method plays an important role. For nanosystem involved chemical processes, such as graphene growth, multiscale simulation methods should be developed to characterize their atomic details. In this review, we review some recent progresses in methodology development for computational characterization of nanosystems. Advanced algorithms and software are essential for us to better understand of the nanoworld.     

聚合物与表面活性剂相互作用的分子模拟研究进展

聚合物与表面活性剂复配体系已广泛应用于医药、生物、石油石化等领域。从微观上认识其相互作用机理对指导其生产实际有着重要作用,因而此方面的研究倍受关注。随着分子模拟技术的发展,聚合物与表面活性剂在分子水平上的相互作用机理研究已经被广泛开展,并获得了大量有用的信息。本文综述了耗散粒子动力学(DPD)和粗粒度分子动力学(CG-MD)在聚合物与表面活性剂相互作用方面的应用,分别对中性聚合物与离子型表面活性剂,以及带相反电荷的聚电解质和表面活性剂在溶液相和界面相的相互作用进行了阐述,并揭示了聚合物/表面活性剂聚集体结构形态的变化规律。     

Conducting the RBD of SARS-CoV-2 Omicron Variant with Phytoconstituents from Euphorbia dendroides to Repudiate the Binding of Spike Glycoprotein Using Computational Molecular Search and Simulation Approach

(1) Background: Natural constituents are still a preferred route for counteracting the outbreak of COVID-19. Essentially, flavonoids have been found to be among the most promising molecules identified as coronavirus inhibitors. Recently, a new SARS-CoV-2 B.1.1.529 variant has spread in many countries, which has raised awareness of the role of natural constituents in attempts to contribute to therapeutic protocols. (2) Methods: Using various chromatographic techniques, triterpenes (1–7), phenolics (8–11), and flavonoids (12–17) were isolated from Euphorbia dendroides and computationally screened against the receptor-binding domain (RBD) of the SARS-CoV-2 Omicron variant. As a first step, molecular docking calculations were performed for all investigated compounds. Promising compounds were subjected to molecular dynamics simulations (MD) for 200 ns, in addition to molecular mechanics Poisson–Boltzmann surface area calculations (MM/PBSA) to determine binding energy. (3) Results: MM/PBSA binding energy calculations showed that compound 14 (quercetin-3-O-β-D-glucuronopyranoside) and compound 15 (quercetin-3-O-glucuronide 6″-O-methyl ester) exhibited strong inhibition of Omicron, with ΔG_binding of −41.0 and −32.4 kcal/mol, respectively. Finally, drug likeness evaluations based on Lipinski’s rule of five also showed that the discovered compounds exhibited good oral bioavailability. (4) Conclusions: It is foreseeable that these results provide a novel intellectual contribution in light of the decreasing prevalence of SARS-CoV-2 B.1.1.529 and could be a good addition to the therapeutic protocol.     

诺氟沙星-DNA复合物的分子动力学模拟

采用分子模建的方法构建了诺氟沙星-DNA复合物的初始结构, 通过2 ns的分子动力学(MD)模拟研究表明: 诺氟沙星能够和双螺旋d[ATATCGATAT]₂形成稳定的复合物, 药物分子可紧密结合在DNA的小沟区域, 并且能够与DNA的鸟嘌呤碱基形成两个稳定的氢键. 在分子水平上提供了诺氟沙星直接与双螺旋DNA相互作用的结构及复合物的动态变化情况.     

Aphrodisiac Performance of Bioactive Compounds from Mimosa pudica Linn.: In Silico Molecular Docking and Dynamics Simulation Approach

Plants and their derived molecules have been traditionally used to manage numerous pathological complications, including male erectile dysfunction (ED). Mimosa pudica Linn. commonly referred to as the touch-me-not plant, and its extract are important sources of new lead molecules in drug discovery research. The main goal of this study was to predict highly effective molecules from M. pudica Linn. for reaching and maintaining penile erection before and during sexual intercourse through in silico molecular docking and dynamics simulation tools. A total of 28 bioactive molecules were identified from this target plant through public repositories, and their chemical structures were drawn using Chemsketch software. Graph theoretical network principles were applied to identify the ideal target (phosphodiesterase type 5) and rebuild the network to visualize the responsible signaling genes, proteins, and enzymes. The 28 identified bioactive molecules were docked against the phosphodiesterase type 5 (PDE5) enzyme and compared with the standard PDE5 inhibitor (sildenafil). Pharmacokinetics (ADME), toxicity, and several physicochemical properties of bioactive molecules were assessed to confirm their drug-likeness property. Molecular dynamics (MD) simulation modeling was performed to investigate the stability of PDE5–ligand complexes. Four bioactive molecules (Bufadienolide (−12.30 kcal mol⁻¹), Stigmasterol (−11.40 kcal mol⁻¹), Isovitexin (−11.20 kcal mol⁻¹), and Apigetrin (−11.20 kcal mol⁻¹)) showed the top binding affinities with the PDE5 enzyme, much more powerful than the standard PDE5 inhibitor (−9.80 kcal mol⁻¹). The four top binding bioactive molecules were further validated for a stable binding affinity with the PDE5 enzyme and conformation during the MD simulation period as compared to the apoprotein and standard PDE5 inhibitor complexes. Further, the four top binding bioactive molecules demonstrated significant drug-likeness characteristics with lower toxicity profiles. According to the findings, the four top binding molecules may be used as potent and safe PDE5 inhibitors and could potentially be used in the treatment of ED.     

Conformational Dynamics of apo‐GlnBP Revealed by Experimental and Computational Analysis

The glutamine binding protein (GlnBP) binds l ‐glutamine and cooperates with its cognate transporters during glutamine uptake. Crystal structure analysis has revealed an open and a closed conformation for apo‐ and holo‐GlnBP, respectively. However, the detailed conformational dynamics have remained unclear. Herein, we combined NMR spectroscopy, MD simulations, and single‐molecule FRET techniques to decipher the conformational dynamics of apo‐GlnBP. The NMR residual dipolar couplings of apo‐GlnBP were in good agreement with a MD‐derived structure ensemble consisting of four metastable states. The open and closed conformations are the two major states. This four‐state model was further validated by smFRET experiments and suggests the conformational selection mechanism in ligand recognition of GlnBP.     

覆盖的氩原子簇过热的分子动力学模拟(英)

通过分子动力学模拟研究了覆盖较高熔点的原子的氩原子簇．原子族由177个氩原子和72个覆盖原子组成．覆盖原子的势能参数ε比氩原子大50％，该原子簇比纯氩原子簇熔点过热2K．模拟结果表明，覆盖的原子簇过热的原因是：在达到熔点之前，体系缺少氩原子构成的自由表面，仍然是覆盖原子的有序表面．     

Rationalization of the Superior Anticancer Activity of Phenanthriplatin: An In-Depth Computational Exploration

In the effort to overcome issues of toxicity and resistance inherent to treatment by the approved platinum anticancer agents, a large number of cisplatin variants continues today to be prepared and tested. One of the applied strategies is to use monofunctional platinum complexes that, unlike traditional bifunctional compounds, are able to form only a single covalent bond with nuclear DNA. Chirality, aquation reaction, interaction with guanine and N-acetyl methionine as well as, intercalation into, binding to and distortion of DNA have been investigated by using both quantum mechanical DFT and molecular dynamics computations aiming at contributing to the elucidation of the molecular mechanism underlying the significantly enhanced spectrum of activity of the monofunctional Pt^II drug phenanthriplatin. Analogous calculations have been performed in parallel for other two less potent monofunctional Pt^II drugs, pyriplatin and enpyriplatin, which show very different cytotoxic effects.     

基于分子模拟的离子液体修饰Porcine Pancreas脂肪酶催化性能和稳定性的相关研究

采用分子模拟手段研究了功能性离子液体[HOOCBMIm]Cl修饰Porcine Pancreas脂肪酶(PPL)结构稳定性与催化性能增强的机理. 在335和300 K下比较研究两种脂肪酶的一系列相互作用特点与结构性质, 包括静电势(electrostatic potential, ESP)、均方根偏差(Root Mean Square Deviation, RMSD)、能量变化、溶剂化面积等等. 分析结果表明: 在335 K下, 修饰后的脂肪酶(Engineered PPL)的RMSD值(0.537 Å)小于未修饰的脂肪酶(Wild-type PPL)的RMSD值(0.68 Å), 同时Engineered PPL的自由能也低于Wild-type PPL的自由能, 说明Engineered PPL的构象更加稳定. 修饰剂的引入使得Engineered PPL的疏水性面积和溶剂可及性面积(Solvent Accessible Surface Area, SASA)增大, 增强了Engineered PPL的稳定性和水解活力. 修饰剂的正电性与修饰位点附近的负电势氨基酸形成静电吸引作用, 优化了蛋白表面电荷的相互作用, 进一步提高了蛋白稳定性; 同时也稳定了蛋白盖子结构的打开状态, 有利于底物进入蛋白空腔催化位点, 实现催化活性提升. 本文从分子水平展示了离子液体修饰脂肪酶并提供了一种解析化学修饰改变酶学性质的方法.     

Structural and Anion Coordination Features of Macrocyclic Polyammonium Cations in the Solid,Solution and Computational Phases

Abstract

The crystal structures of two hexaaza macrocycles 1,4,7,12,15,18-hexaazacyclodocosane ([22]N₆:1-6H⁺, 6C1^?) and 1,13-dioxa-4,7,10,16,19,22-hexaazacyclotetraeicosane ([24]N₆O₂:2-6H⁺,6CI^?) as their hexa-hydrochloride salts have been determined. 1-6H⁺ binds specifically two CI^? anions above and below the almost planar hexaammonium macrocycle yielding a dinuclear CI^? complex. The hexacation 2-6H⁺ on the other hand interacts preferentially with three CI^? anions of the six present in the solid state. Among the three closest anions, one of them, interacting with four ammonium groups, is located in the centre of the macrocycle which adopts a “pocket-like” conformation. Potentiometric and ³⁵CI NMR experiments demonstrate that 2-6H⁺ also binds CI^? in aqueous solution. Subsequent extensive molecular dynamics computational studies starting from X-ray coordinates show that the solid state structure is representative of the solution conformations for I-6H⁺, whereas the conformations of 2-6H⁺ are strongly affected by intramolecular interactions between the ammonium centres and O-atoms of the ether linkage as well as by intermolecular interactions with H₂O molecules and CI^? counterions.     

Performance evaluation of the zero‐multipole summation method in modern molecular dynamics software

The zero‐multiple summation method (ZMM) is a cutoff‐based method for calculating electrostatic interactions in molecular dynamics simulations, utilizing an electrostatic neutralization principle as a physical basis. Since the accuracies of the ZMM have been revealed to be sufficient in previous studies, it is highly desirable to clarify its practical performance. In this paper, the performance of the ZMM is compared with that of the smooth particle mesh Ewald method (SPME), where the both methods are implemented in molecular dynamics software package GROMACS. Extensive performance comparisons against a highly optimized, parameter‐tuned SPME implementation are performed for various‐sized water systems and two protein–water systems. We analyze in detail the dependence of the performance on the potential parameters and the number of CPU cores. Even though the ZMM uses a larger cutoff distance than the SPME does, the performance of the ZMM is comparable to or better than that of the SPME. This is because the ZMM does not require a time‐consuming electrostatic convolution and because the ZMM gains short neighbor‐list distances due to the smooth damping feature of the pairwise potential function near the cutoff length. We found, in particular, that the ZMM with quadrupole or octupole cancellation and no damping factor is an excellent candidate for the fast calculation of electrostatic interactions. © 2018 Wiley Periodicals, Inc.     

基于拉伸分子动力学模拟的黄嘌呤氧化酶抑制剂解离途径的理论研究

采用拉伸分子动力学模拟的方法研究了黄嘌呤氧化酶(Xanthine oxidase, XO)抑制剂别嘌呤醇(Allopurinol)和葛根素(Puerarin)从XO离去通道解离的动态过程. 分子对接结果表明, 别嘌呤醇和葛根素均结合在XO的钼蝶呤中心(Molybdopterin, Mo-pt); 丙氨酸扫描的结果显示, Val789, Arg880, Phe911, Phe914和Val1081在XO与抑制剂的结合中起到非常重要的作用. 拉伸分子动力学模拟结果显示, 相比于葛根素, 别嘌呤醇需要更大的外力和更长的时间才能从XO中解离, 拉伸过程中Arg880, Phe1009, Thr1010, Val1011和Ala1079均对维持2种复合物的结构稳定起到重要作用, Phe649和Phe1013在抑制剂解离过程中起到门控的作用, His875起到阻碍抑制剂解离的作用.     

Computational study of the catalytic domain of human neutrophil collagenase. specific role of the S3 and S'3 subsites in the interaction with a phosphonate inhibitor

Human neutrophil collagenase (HNC, MMP-8) is one of the target enzymes for drug treatment of pathologic extracellular matrix degradation. Peptidomimetic inhibitors bind in the S-side of the enzyme active site occupying the S ₁primary specificity pocket by their large hydrophobic side-chains. The crystal structure of the complex between the catalytic domain of MMP-8 and Pro-Leu-l-Trp^P(OH)₂(PLTP) showed that this phosphonate inhibitor binds in the S side of the active site. This finding was unexpected since it represents the first example of accommodation of the bulky Trp indolyl chain in the S₁rather than in the S ₁subsite. Dynamical and structural factors favouring this uncommon mode of binding were therefore investigated.MD simulations performed on the uncomplexed enzyme show that its structure in aqueous solution is only slightly different from the crystal structure found in the complex with PLTP. ED analysis of the MD simulations, performed on PLTP alternatively interacting with the S- or S-side of the active site, shows that the enzyme fluctuation increases in both cases. The main contribution to the overall enzyme fluctuation is given by the loop 164–173. The fluctuation of this loop is spread over more degrees of freedom when PLTP interacts with the S-side. This dynamical factor can enhance the preference of PLTP for the S subsites of MMP-8. MD simulations also show that ligation of PLTP in the S subsites is further favoured by better zinc chelation, a cation- interaction at the S₃subsite and unstrained binding conformations. The role of the S₃, S ₃and S ₁subsites in determining the inhibitor binding is discussed.     

Molecular Dynamic Simulation of Side-Chain Liquid Crystalline Elastomer

Summary: Molecular dynamic simulation of side chain liquid crystalline elastomer has been carried out. As an initial state a flexible polymer network in a low molecular liquid-crystal (LC) solvent was used. The LC solvent comprises of anisotropic rod-like semiflexible linear molecules (mesogens) composed of particles bonded into the chain by FENE potential. Rigidity of LC molecules was induced by a bending potential. All interactions between nonbonded particles are described by a repulsive Lennard-Jones potential. For the systems with different values of density and order parameter obtained after sufficiently long trajectory the attachment of ends of mesogens to the polymer network was simulated. The kinetic of the process of mesogens attachment to network was studied as well as morphology of attachment. The structural and dynamical behaviour of side chain LC elastomer was studied and compared with systems of polymer network in low molecular LC solvent.     

An Effective Simulation of Aqueous Micellar Aggregates by Computational Models

Summary We have computationally studied the interaction modes, localization and orientation of a benzene (Bz) molecule on the surface of micelles formed by cetyltrimethylammonium salts CTAX. Experimental ¹H-NMR data on complexation shifts induced by Bz on the polar head hydrogens and on the adjacent methylene hydrogens of CTAX have been interpreted using a computational approach that combines an automatic molecular docking procedure with a calculation module that accounts for NMR complexation shifts due to ring current diamagnetic anisotropy. Three different models were used to reduce the complexity of the micellar system. Computational results, in good agreement with available experimental data, point to a preferential localization of the Bz molecule along the CTAX alkyl tail, about 3.9 Å away from the charged nitrogen. The Bz molecular plane is predicted perpendicular to the C-H bonds of the alkyl tail. The good results obtained with the simplest model suggest that it could be used to study more complex systems involving surfactants endowed with molecular recognition or catalytic abilities.     

基于GROMACS软件的本科生酶工程创新实验项目设计*——微生物谷氨酰胺转胺酶在水溶液中的分子动力学模拟

基于分子动力学模拟软件GROMACS设计了微生物谷氨酰胺转胺酶在不同温度水环境下的分子动力学模拟实验,通过计算模拟过程中酶蛋白主链动力学,分子内氢键数目,回转半径以及溶剂可接触表面积的变化,分析温度对酶的结构与功能造成的影响。该模拟实验可帮助学生:(1)掌握蛋白质分子在水溶液中动力学模拟的方法;(2)理解温度对酶结构稳定性和活性造成的影响;(3)了解分子运动特性的生物学的意义;(4)学习酶工程研究的新手段。     

Elucidating the Glucokinase Activating Potentials of Naturally Occurring Prenylated Flavonoids: An Explicit Computational Approach

Glucokinase activators are considered as new therapeutic arsenals that bind to the allosteric activator sites of glucokinase enzymes, thereby maximizing its catalytic rate and increasing its affinity to glucose. This study was designed to identify potent glucokinase activators from prenylated flavonoids isolated from medicinal plants using molecular docking, molecular dynamics simulation, density functional theory, and ADMET analysis. Virtual screening was carried out on glucokinase enzymes using 221 naturally occurring prenylated flavonoids, followed by molecular dynamics simulation (100 ns), density functional theory (B3LYP model), and ADMET (admeSar 2 online server) studies. The result obtained from the virtual screening with the glucokinase revealed arcommunol B (−10.1 kcal/mol), kuwanon S (−9.6 kcal/mol), manuifolin H (−9.5 kcal/mol), and kuwanon F (−9.4 kcal/mol) as the top-ranked molecules. Additionally, the molecular dynamics simulation and MM/GBSA calculations showed that the hit molecules were stable at the active site of the glucokinase enzyme. Furthermore, the DFT and ADMET studies revealed the hit molecules as potential glucokinase activators and drug-like candidates. Our findings suggested further evaluation of the top-ranked prenylated flavonoids for their in vitro and in vivo glucokinase activating potentials.     

Computational Insight to Improve the Thermal Isomerisation Performance of Overcrowded Alkene‐Based Molecular Motors through Structural Redesign

Synthetic overcrowded alkene‐based molecular motors achieve 360° unidirectional rotary motion of one motor half (rotator) relative to the other (stator) through sequential photochemical and thermal isomerisation steps. In order to facilitate and expand the use of these motors for various applications, it is important to investigate ways to increase the rates and efficiencies of the reactions governing the rotary motion. Here, we use computational methods to explore whether the thermal isomerisation performance of some of the fastest available motors of this type can be further improved by reducing the sizes of the motor halves. Presenting three new redesigned motors that combine an indanylidene rotator with a cyclohexadiene, pyran or thiopyran stator, we first use multiconfigurational quantum chemical methods to verify that the photoisomerisations of these motors sustain unidirectional rotary motion. Then, by performing density functional calculations, we identify both stepwise and concerted mechanisms for the thermal isomerisations of the motors and show that the rate‐determining free‐energy barriers of these processes are up to 25 kJ mol^?1 smaller than those of the original motors. Furthermore, the thermal isomerisations of the redesigned motors proceed in fewer steps. Altogether, the results suggest that the redesigned motors are useful templates for improving the thermal isomerisation performance of existing overcrowded alkene‐based motors.     

Mollusc-Derived Brominated Indoles for the Selective Inhibition of Cyclooxygenase: A Computational Expedition

Inflammation plays an important role in different chronic diseases. Brominated indoles derived from the Australian marine mollusk Dicathais orbita (D. orbita) are of interest for their anti-inflammatory properties. This study evaluates the binding mechanism and potentiality of several brominated indoles (tyrindoxyl sulfate, tyrindoleninone, 6-bromoisatin, and 6,6′-dibromoindirubin) against inflammatory mediators cyclooxygenases-1/2 (COX-1/2) using molecular docking, followed by molecular dynamics simulation, along with physicochemical, drug-likeness, pharmacokinetic (pk), and toxicokinetic (tk) properties. Molecular docking identified that these indole compounds are anchored, with the main amino acid residues, positioned in the binding pocket of the COX-1/2, required for selective inhibition. Moreover, the molecular dynamics simulation based on root mean square deviation (RMSD), radius of gyration (Rg), solvent accessible surface area (SASA), and root mean square fluctuation (RMSF) analyses showed that these natural brominated molecules transit rapidly to a progressive constant configuration during binding with COX-1/2 and seem to accomplish a consistent dynamic behavior by maintaining conformational stability and compactness. The results were comparable to the Food and Drug Administration (FDA)-approved selective COX inhibitor, aspirin. Furthermore, the free energy of binding for the compounds assessed by molecular mechanics–Poisson–Boltzmann surface area (MM–PBSA) confirmed the binding capacity of indoles towards COX-1/2, with suitable binding energy values except for the polar precursor tyrindoxyl sulfate (with COX-1). The physicochemical and drug-likeness analysis showed zero violations of Lipinski’s rule, and the compounds are predicted to have excellent pharmacokinetic profiles. These indoles are projected to be non-mutagenic and free from hepatotoxicity, with no inhibition of human ether-a-go–go gene (hERG) I inhibitors, and the oral acute toxicity LD₅₀ in rats is predicted to be similar or lower than aspirin. Overall, this work has identified a plausible mechanism for selective COX inhibition by natural marine indoles as potential therapeutic candidates for the mitigation of inflammation.