Molecular Dynamics Simulations of Cellulose Oligomers: Conformational Analysis

Summary: The results of classical molecular simulations of cellulose oligomers are presented here. The conformations of the chains in the high temperature melt, room temperature quenched melt and gas phase are compared with respect to various geometrical parameters including square end‐to‐end distances, glycosidic link torsion correlations, ring puckering and hydrogen bonding. The cellulose oligomer melts were relaxed at 800 K with molecular dynamics, and then cooled down in three different ways to obtain dense amorphous systems at 500 K and at room temperature. The sample resulting from the quench (step) shows too much similarity with the melt at 800 K. The two other cooling schemes (ramp, 2ramps) give very similar results for all quantities investigated. The relevance of previous single molecule calculations with respect to the dense amorphous systems is called into question. Comparisons between the chains in the dense systems and those in the gas phase reveal that, even for these relatively short stiff chains, differences exist in the preferred conformations. At high temperatures, where both systems are in equilibrium, the distribution of square end‐to‐end distances are both fairly smooth, but the gas phase clearly prefers more compact conformations. At 300 K, the differences are exacerbated as the equilibrium distribution for the gas phase shows a high proportion of folded conformers, whereas the nonequilibrium quenched systems necessarily retain the extended envelope of the higher temperature. Differences are also evident in the puckering, the rotation of the hydroxymethyl groups and the pattern of hydrogen bonds.

The probability density distribution for the square end‐to‐end distance for octaose in the gas phase (light line) and in the dense phase (dark line) at 300 K.     

DNA Structural Changes Under Different Stretching Methods Studied By Molecular Dynamics Simulations

We present a molecular dynamics simulation study of 22‐mer DNA conformational variations obtained by stretching both 3′‐termini and both 5′‐termini. Stretching 3′‐termini by 3.5 nm required 142 kJ mol^?1 and the force plateau was ～80 pN, whereas stretching 5′‐termini by the same length required 190 kJ mol^?1 and the force plateau was ～100 pN. Stretching 3′‐termini led to a larger untwisting of the double helix and the successive base pairs rolled to the side of the DNA minor groove, while stretching 5′‐termini resulted in the base pairs rolling to the major groove side and reducing of the diameter of DNA molecule. The most distinctive difference between stretching 3′‐termini and 5′‐termini was that at the force plateau region stretching the 5′‐termini resulted in breakage of the base pairs, which considerably disturbed the structure of the DNA double helix. All of the variations of base rotation and translation for both stretching methods took place when the relative length of DNA l was longer than 1.2, which was the point the force plateau appeared.     

Molecular Dynamics Simulations of Polymer Translocations

Summary: Molecular dynamics simulation studies of the translocation of charged homopolymers of length, N, driven by an electric potential gradient through a channel have been performed. We find that the translocation time, τ, displays an inverse power dependence on the temperature of the simulation τ ∼ (T − T₀)^−7/4, which is in very good agreement with experimental results. In addition, the dependence of τ on the driving field strength and the velocity of translocation on the polymer length N have also been obtained. The results suggest that such minimalist models are useful in modelling biological processes and that the molecular dynamics method is a suitable approach for carrying out these simulations.

Snapshot of the polymer during the simulation.     

Representation of Hydrogen Atoms in Molecular Dynamics Simulations: The Influence on the Computed Properties of Thin Polystyrene Films

The united atoms (UA) and dummy hydrogen atom (DHA) approaches for molecular dynamics simulations of the interface between oxidized atactic polystyrene (aPS) thin films and water are compared. For both oxidized and non‐oxidized aPS films the polymer density profile decays steepest when using the UA model. The surface roughness of the aPS film and the ordering of the phenyl rings near the surface decrease upon changing from vacuum to water for the UA, but not for the DHA model. This also supports the fact that the non‐oxidized aPS films modeled in DHA representation become less hydrophobic. The water structure close to the interface also suggests that the aPS films modeled using UA are more hydrophobic compared to the aPS films modeled with DHA in the phenyl rings.

     

Solvent‐Dependent Structure Formation in Drying P3HT:PCBM Films Studied by Molecular Dynamics Simulations

Phase separation in the donor‐acceptor blend poly(3‐hexylthiophene‐2,5‐diyl):[6,6]‐phenyl‐C61‐butyric acid methyl ester (P3HT:PCBM) during evaporation of a solvent using coarse‐grained molecular dynamics simulations is studied here. To this end, an equilibrated P3HT:PCBM:solvent mixture is placed in an elongated simulation box, after which solvent molecules are removed at regular time intervals from a region above the film. Three often‐used solvents are considered: chloroform (CFM), chlorobenzene (CLB), and orthodichlorobenzene (oDCB). The coarse‐grained solvent–solvent interaction parameters are tuned to reproduce the atmospheric boiling temperatures, while the PCBM–solvent interaction parameters are tuned to reproduce the PCBM solubilities. Other parameters are taken from the literature. During evaporation, the formation of a crust that is depleted of solvent, in which aggregation of P3HT and PCBM occurs, is observed. In agreement with experiment, the top region of the dry film is rich in PCBM for the cases of CLB and oDCB, and rich in P3HT for the case of CFM, while the very top layer of the film is always rich in P3HT. This vertical separation is ascribed to a competition between the tendency of P3HT to move to the surface due to its low surface energy and the different tendencies of PCBM to be dragged along to the surface by the evaporating solvent depending on its solubility. Also in agreement with experiment, the P3HT–PCBM interface area is larger for CLB and oDCB than for CFM. For CLB and oDCB, an indication for a spinodal P3HT–PCBM decomposition starting from the top and bottom surface is found, whereas for CFM the phase separation appears to be initiated in the bulk of the film.

     

Molecular Dynamics Simulations Study of the Interactions between Human Dipeptidyl-Peptidase III and Two Substrates

Human dipeptidyl-peptidase III (hDPP III) is capable of specifically cleaving dipeptides from the N-terminal of small peptides with biological activity such as angiotensin II (Ang II, DRVYIHPF), and participates in blood pressure regulation, pain modulation, and the development of cancers in human biological activities. In this study, 500 ns molecular dynamics simulations were performed on free-hDPP III (PDB code: 5E33), hDPP III-Ang II (PDB code: 5E2Q), and hDPP III-IVYPW (PDB code: 5E3C) to explore how these two peptides affect the catalytic efficiency of enzymes in terms of the binding mode and the conformational changes. Our results indicate that in the case of the hDPP III-Ang II complex, subsite S1 became small and hydrophobic, which might be propitious for the nucleophile to attack the substrate. The structures of the most stable conformations of the three systems revealed that Arg421-Lys423 could form an α-helix with the presence of Ang II, but only part of the α-helix was produced in hDPP III-IVYPW. As the hinge structure in hDPP III, the conformational changes that took place in the Arg421-Lys423 residue could lead to the changes in the shape and space of the catalytic subsites, which might allow water to function as a nucleophile to attack the substrate. Our results may provide new clues to enable the design of new inhibitors for hDPP III in the future.     

自组装的分子动力学模拟

简要回顾了近年来国内外分子动力学模拟自组装的研究,对已报道的建模方法、可视化表现以及相关应用略作概述,并以此为基础对自组装过程的分子动力学模拟研究所面临的问题和尚需深入的内容进行了讨论。基于自组装、相变和涨落的固有联系,提出了以研究波动为手段,和以频率相关热容为研究对象的探索方向。希望能够为分子动力学模拟推动自组装研究提供有益的参考。     

MDMS: Software Facilitating Performing Molecular Dynamics Simulations

Molecular Dynamics Made Simple (MDMS) is software that facilitates performing molecular dynamics (MD) simulations of solvated protein/protein–ligand complexes with Amber, one of the most popular MD codes. It guides users through the whole process of running MD starting with choosing a protein structure, preparing the model, parametrization of the system, establishing parameters for controlling MD, and finally running simulations. By accommodating every step required for running MD, this software ensures that the simulations performed by a user will provide as realistic insight as it is possible. Its sequential structure and a text-based interface ensure ease of use, while the flexibility required for complex cases is still preserved. MDMS also provides a very time-efficient and streamlined method to start MD simulations, which makes it a feasible tool for both novices and experienced computational chemists. © 2019 Wiley Periodicals, Inc.     

Molecular Dynamics Simulations of Energetic Solids

A continuing objective in the area of energetic materials is to reduce sensitivity toward impact and shock. One approach is to develop a better understanding of how factors related to the crystal lattice, e.g., defects, influence the initiation and propagation of detonation. Molecular dynamics is a useful tool for this purpose. This paper presents an overview of molecular dynamics treatments of energetic solids. Some of these have simulated initiation and propagation in idealized systems; others have focused on developing a satisfactory procedure for describing molecular crystals of practical significance. Our emphasis in this discussion is on the progress that has been made along the second lines.     

Protein-Protein Interactions: Insight from Molecular Dynamics Simulations and Nanoparticle Tracking Analysis

Protein-protein interaction plays an essential role in almost all cellular processes and biological functions. Coupling molecular dynamics (MD) simulations and nanoparticle tracking analysis (NTA) assay offered a simple, rapid, and direct approach in monitoring the protein-protein binding process and predicting the binding affinity. Our case study of designed ankyrin repeats proteins (DARPins)—AnkGAG1D4 and the single point mutated AnkGAG1D4-Y56A for HIV-1 capsid protein (CA) were investigated. As reported, AnkGAG1D4 bound with CA for inhibitory activity; however, it lost its inhibitory strength when tyrosine at residue 56 AnkGAG1D4, the most key residue was replaced by alanine (AnkGAG1D4-Y56A). Through NTA, the binding of DARPins and CA was measured by monitoring the increment of the hydrodynamic radius of the AnkGAG1D4-gold conjugated nanoparticles (AnkGAG1D4-GNP) and AnkGAG1D4-Y56A-GNP upon interaction with CA in buffer solution. The size of the AnkGAG1D4-GNP increased when it interacted with CA but not AnkGAG1D4-Y56A-GNP. In addition, a much higher binding free energy (∆GB) of AnkGAG1D4-Y56A (−31 kcal/mol) obtained from MD further suggested affinity for CA completely reduced compared to AnkGAG1D4 (−60 kcal/mol). The possible mechanism of the protein-protein binding was explored in detail by decomposing the binding free energy for crucial residues identification and hydrogen bond analysis.     

Determination of volume fractions and ligand layer thickness of polymer/CdSe quantum dot blend films by effective medium approximations

We investigate hybrid organic/inorganic films using different polymers and CdSe quantum dots (QD) and nanorods (NR) with hexanoic acid (HA)‐treated hexadecylamine (HDA) or pyridine as the capping ligands. The volume ratios of the polymer:nanoparticle (NP) blends are studied by spectroscopic ellipsometry and transmission intensity data. Effective medium approximation based on the results of the pristine films is applied. With this routine, the polymer/NP volume ratio of the blend can be identified. In combination with the mass ratio of the components, the mass density of the NP including the inorganic crystalline core and the organic ligand layer is obtained. A geometrical model for QD and NR allows for the estimation of the ligand layer thickness. We find pyridine and HDA after HA treatment to be 0.9 and 0.6 nm on the QD surface, respectively. By contrast, the effective thickness of the organic ligand is 3.0 nm on the investigated NR. In both cases, the organic layer is thicker than a monolayer of the expected pyridine due to the presence of extant synthesis ligands as a result of incomplete ligand exchange. © 2011 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 000: 000–000, 2011     

Crack Formation and Propagation in Molecular Dynamics Simulations of Polymer Liquid Crystals

In recent papers we have used statistical mechanics to predict multiple phase formation in polymer liquid crystals (PLCs).^[1, 2] Now we have performed molecular dynamics simulations of PLC copolymers as materials consisting of LC islands in flexible matrices. A method for creating such materials on a computer is described. The overall concentration of the LC units, island size, and spatial distribution of the islands (random, in rows, and evenly distributed throughout the material) were varied. Crack formation and propagation as a function of these parameters were investigated. The local concentration of LC units in each chain has been defined. We found that the probability of a crack initiation site goes symbiotically with the local LC concentration. The first small crack is sometimes a part of the path through which the material breaks, however, although several small cracks may evolve at first, some of these never evolve into larger cracks since crack arrest occurs. The results can be used for creation of real materials with improved mechanical properties.     

Molecular Dynamics Simulations of Helium Permeation in Polyimides with a Bulky Dianhydride and a Fluorinated Diamine

Fully‐atomistic molecular dynamics (MD) simulations have been carried out to model helium transport through four different glassy polyimides. While the polymer matrices had been pre‐validated, specific parameters and combination rules were used here in order to describe helium‐helium and helium‐polymer interactions. Gas permeabilities are in very good agreement with experimental evidence. Two ways to decrease chain cohesion and improve gas transport were considered – the replacement of an ODPA by a bulky BCDA dianhydride, and the substitution of a site on an ODA diamine by a CF₃. The fluorinated polyimide appears to be the most promising material with more heterogeneity in the void‐space distribution, the highest model permeability and fewer constraints from an experimental point of view.

     

谷氨酰胺结合蛋白的分子动力学模拟和自由能计算

谷氨酰胺结合蛋白(Glutamine-binding protein, GlnBp)是大肠杆菌透性酶系统中一个细胞外液底物专一性结合蛋白, 对于细胞外液中谷氨酰胺(Gln)的运输和传递至关重要. 本文运用分子动力学(Molecular dynamics, MD)模拟采样, 考察了GlnBp关键残基与底物Gln之间的相互作用和GlnBp两条铰链的功能差别; 并采用MM-PBSA方法计算了GlnBp与底物Gln的结合自由能. 结果表明: Ph13, Phe50, Thr118和Ile69与底物Gln的范德华相互作用和Arg75, Thr70, Asp157, Gly68, Lys115, Ala67, His156与底物Gln的静电相互作用是结合Gln的主要推动力; 复合物的铰链区85～89柔性大, 对构象开合提供了结构基础; 而铰链区181～185柔性小, 其作用更多是在功能上把底物Gln限制在口袋中; 自由能预测值与实验值吻合. 本研究很好地解释了GlnBp结构与功能的关系, 为进一步了解GlnBp的开合及转运Gln的机制提供了重要的结构信息.     

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.     

The Interplay of Cholesterol and Ligand Binding in hTSPO from Classical Molecular Dynamics Simulations

The translocator protein (TSPO) is a 18kDa transmembrane protein, ubiquitously present in human mitochondria. It is overexpressed in tumor cells and at the sites of neuroinflammation, thus representing an important biomarker, as well as a promising drug target. In mammalian TSPO, there are cholesterol–binding motifs, as well as a binding cavity able to accommodate different chemical compounds. Given the lack of structural information for the human protein, we built a model of human (h) TSPO in the apo state and in complex with PK11195, a molecule routinely used in positron emission tomography (PET) for imaging of neuroinflammatory sites. To better understand the interactions of PK11195 and cholesterol with this pharmacologically relevant protein, we ran molecular dynamics simulations of the apo and holo proteins embedded in a model membrane. We found that: (i) PK11195 stabilizes hTSPO structural fold; (ii) PK11195 might enter in the binding site through transmembrane helices I and II of hTSPO; (iii) PK11195 reduces the frequency of cholesterol binding to the lower, N–terminal part of hTSPO in the inner membrane leaflet, while this impact is less pronounced for the upper, C–terminal part in the outer membrane leaflet, where the ligand binding site is located; (iv) very interestingly, cholesterol most frequently binds simultaneously to the so-called CRAC and CARC regions in TM V in the free form (residues L150–X–Y152–X(3)–R156 and R135–X(2)–Y138–X(2)–L141, respectively). However, when the protein is in complex with PK11195, cholesterol binds equally frequently to the CRAC–resembling motif that we observed in TM I (residues L17–X(2)–F20–X(3)–R24) and to CRAC in TM V. We expect that the CRAC–like motif in TM I will be of interest in future experimental investigations. Thus, our MD simulations provide insight into the structural features of hTSPO and the previously unknown interplay between PK11195 and cholesterol interactions with this pharmacologically relevant protein.     

Order and Phase Behavior of a Cylinder Forming Diblock Copolymers and Nano‐Particles Mixture in Confinement: A Molecular Dynamics Study

We study a coarse grained model of cylinder forming diblock copolymers and nano‐particles (NPs) mixture confined between Lennard–Jones hard walls. Two models for non‐selective interactions between monomers and NPs are applied. In the case of purely repulsive interactions between NPs and monomers (athermal case) strong segregation of NPs at the film surfaces and the formation of droplets of particles inside the copolymer film can be observed. For weakly attractive interactions between NPs and monomers (thermal case) formation of droplets of particles disappears and segregation on the film surfaces depend on temperature. The uptake of NPs by the copolymer film in the thermal case displays a non‐monotonic dependence on temperature which can be qualitatively explained by a mean‐field model. In both cases of non‐selective interactions NPs are preferentially localized at the interface between the microphase domains.

     

洋刀豆脲酶与抑制剂相互作用的分子对接和分子动力学研究

通过洋刀豆脲酶抑制剂的筛选实验得到具有较好抑制活性的化合物2-乙酰基-γ-丁内酯(COM), 其半数抑制浓度在微摩尔浓度级别(IC₅₀＝375 μmol•L^－l). 在此基础上, 使用分子对接和分子动力学(MD)模拟的方法研究洋刀豆脲酶与抑制剂乙酰氧肟酸(AHA)及活性化合物COM之间的相互作用. 用Gold3.0程序将两个小分子与洋刀豆脲酶的晶体结构进行对接, 对接得到的复合物模型使用Amber程序进行MD模拟研究. 模拟过程中, 脲酶结构中的双核镍离子活性中心选用non-bonded模型. 研究结果显示: AHA与洋刀豆脲酶结合时, Ni(1)和Ni(2)均为五配位|COM与洋刀豆脲酶结合时Ni(1)为五配位, Ni(2)为六配位的结合模型更加合理. 这些研究为了解洋刀豆脲酶与抑制剂之间的相互作用提供了重要的参考信息.