Study of Endogen Substrates,Drug Substrates and Inhibitors Binding Conformations on MRP4 and Its Variants by Molecular Docking and Molecular Dynamics

Multidrug resistance protein-4 (MRP4) belongs to the ABC transporter superfamily and promotes the transport of xenobiotics including drugs. A non-synonymous single nucleotide polymorphisms (nsSNPs) in the ABCC4 gene can promote changes in the structure and function of MRP4. In this work, the interaction of certain endogen substrates, drug substrates, and inhibitors with wild type-MRP4 (WT-MRP4) and its variants G187W and Y556C were studied to determine differences in the intermolecular interactions and affinity related to SNPs using protein threading modeling, molecular docking, all-atom, coarse grained, and umbrella sampling molecular dynamics simulations (AA-MDS and CG-MDS, respectively). The results showed that the three MRP4 structures had significantly different conformations at given sites, leading to differences in the docking scores (DS) and binding sites of three different groups of molecules. Folic acid (FA) had the highest variation in DS on G187W concerning WT-MRP4. WT-MRP4, G187W, Y556C, and FA had different conformations through 25 ns AA-MD. Umbrella sampling simulations indicated that the Y556C-FA complex was the most stable one with or without ATP. In Y556C, the cyclic adenosine monophosphate (cAMP) and ceefourin-1 binding sites are located out of the entrance of the inner cavity, which suggests that both cAMP and ceefourin-1 may not be transported. The binding site for cAMP and ceefourin-1 is quite similar and the affinity (binding energy) of ceefourin-1 to WT-MRP4, G187W, and Y556C is greater than the affinity of cAMP, which may suggest that ceefourin-1 works as a competitive inhibitor. In conclusion, the nsSNPs G187W and Y556C lead to changes in protein conformation, which modifies the ligand binding site, DS, and binding energy.     

Using “Threading Followed by Shrinking” to Synthesize Highly Stable Dialkylammonium‐Ion‐Based Rotaxanes

Herein, we report a “threading followed by shrinking” approach for the synthesis of rotaxanes by using an “oxygen‐deficient” macrocycle that contained two arylmethyl sulfone units and the dumbbell‐shaped salt bis(3,5‐dimethylbenzyl)ammonium tetrakis(3,5‐trifluoromethylphenyl)borate as the host and guest components, respectively. The extrusion of SO₂ from both of the arylmethyl sulfone units of the macrocyclic component in the corresponding [2]pseudorotaxane resulted in a [2]rotaxane that was sufficiently stable to maintain its molecular integrity in CD₃SOCD₃ at 393 K for at least 5 h.     

蓝宝石衬底上GaN/AlxGa1-xN超晶格插入层对AlxGa1-xN外延薄膜应变及缺陷密度的影响

室温300K下,由于Al_xGa_1-xN的带隙宽度可以从GaN的3.42eV到AlN的6.2eV之间变化,所以Al_xGa_1-xN是紫外光探测器和深紫外LED所必需的外延材料.高质量高铝组分Al_xGa_1-xN材料生长的一大困难就是Al_xGa_1-xN与常用的蓝宝石衬底之间大的晶格失配和热失配.因而采用MOCVD在GaN/蓝宝石上生长的Al_xGa_1-xN薄膜由于受张应力作用非常容易发生龟裂.GaN/Al_xGa_1-xN超晶格插入层技术是释放应力和减少Al_xGa_1-xN薄膜中缺陷的有效方法.研究了GaN/Al_xGa_1-xN超晶格插入层对GaN/蓝宝石上Al_xGa_1-xN外延薄膜应变状态和缺陷密度的影响.通过拉曼散射探测声子频率从而得到材料中的残余应力是一种简便常用的方法,Al_xGa_1-xN外延薄膜的应变状态可通过拉曼光谱测量得到.Al_xGa_1-xN外延薄膜的缺陷密度通过测量X射线衍射得到.对于具有相同阱垒厚度的超晶格,例如4nm/4nm,5nm/5nm,8nm/8nm的GaN/Al_0.3Ga_0.7N超晶格,研究发现随着超晶格周期厚度的增加Al_xGa_1-xN外延薄膜缺陷密度降低,Al_xGa_1-xN外延薄膜处于张应变状态,且5nm/5nmGaN/Al_0.3Ga_0.7N超晶格插入层Al_xGa_1-xN外延薄膜的张应变最小.在保持5nm阱宽不变的情况下,将垒宽增大到8nm,即十个周期的5nm/8nmGaN/Al_0.3Ga_0.7N超晶格插入层使Al_xGa_1-xN外延层应变状态由张应变变为压应变.由X射线衍射结果计算了Al_xGa_1-xN外延薄膜的刃型位错和螺型位错密度,结果表明超晶格插入层对螺型位错和刃型位错都有一定的抑制效果.透射电镜图像表明超晶格插入层使位错发生合并、转向或是使位错终止,且5nm/8nmGaN/Al_0.3Ga_0.7N超晶格插入层导致Al_xGa_1-xN外延薄膜中的刃型位错倾斜30°左右,释放一部分压应变.     

Q-Dock: Low-resolution flexible ligand docking with pocket-specific threading restraints

The rapidly growing number of theoretically predicted protein structures requires robust methods that can utilize low-quality receptor structures as targets for ligand docking. Typically, docking accuracy falls off dramatically when apo or modeled receptors are used in docking experiments. Low-resolution ligand docking techniques have been developed to deal with structural inaccuracies in predicted receptor models. In this spirit, we describe the development and optimization of a knowledge-based potential implemented in Q-Dock, a low-resolution flexible ligand docking approach. Self-docking experiments using crystal structures reveals satisfactory accuracy, comparable with all-atom docking. All-atom models reconstructed from Q-Dock's low-resolution models can be further refined by even a simple all-atom energy minimization. In decoy-docking against distorted receptor models with a root-mean-square deviation, RMSD, from native of approximately 3 A, Q-Dock recovers on average 15-20% more specific contacts and 25-35% more binding residues than all-atom methods. To further improve docking accuracy against low-quality protein models, we propose a pocket-specific protein-ligand interaction potential derived from weakly homologous threading holo-templates. The success rate of Q-Dock employing a pocket-specific potential is 6.3 times higher than that previously reported for the Dolores method, another low-resolution docking approach.     

基于三维不对称主体的客体方向选择性穿线作用及其组装体的构建

在主客体化学中,控制络合过程的异构化现象不仅可以简化和调整所构建的组装体的结构,而且对其顺利执行作为分子机器时的功能也具有极其重要的意义。具有三维不对称结构的主体与线性不对称客体络合时,由于客体穿线方向的不同会导致方向性异构体的形成。这一现象引起了研究者们的兴趣,并对如何通过理性设计主客体的结构来控制客体穿线的方向和选择性进行了研究。本文综述环糊精、杯芳烃及三蝶烯衍生大环等具有三维不对称结构的大环主体与线性不对称客体之间的方向选择性络合作用以及方向性组装体的构建,并立足于该领域的发展现状,对其前景和应用进行了展望。     

The stress birefringence images of low angle grain boundaries in 6H‐SiC single crystals

Low angle grain boundaries, also referred to as domain walls, is one of the major structural defects in c‐axis physical vapor transport (PVT) grown hexagonal Silicon Carbide. To investigate the nature of the low angle boundaries, polarized optical microscope was used. The low angle boundary gives bright stress birefringence images under polarizing optical microscope. Periodic extinction of the stress birefringence images occurs when the (0001)‐face SiC is rotated under polarizing optical microscope. The micro‐structure of the low angle boundary is proposed. Using dislocation elastic theory, it is theoretically confirmed that the domains consist of uniform pure edge dislocations with Burgers vectors perpendicular to the dislocation arrays. The simulation results coincide with the experimental observations.     

Q‐DockLHM: Low‐resolution refinement for ligand comparative modeling

The success of ligand docking calculations typically depends on the quality of the receptor structure. Given improvements in protein structure prediction approaches, approximate protein models now can be routinely obtained for the majority of gene products in a given proteome. Structure‐based virtual screening of large combinatorial libraries of lead candidates against theoretically modeled receptor structures requires fast and reliable docking techniques capable of dealing with structural inaccuracies in protein models. Here, we present Q‐Dock^LHM, a method for low‐resolution refinement of binding poses provided by FINDSITE^LHM, a ligand homology modeling approach. We compare its performance to that of classical ligand docking approaches in ligand docking against a representative set of experimental (both holo and apo) as well as theoretically modeled receptor structures. Docking benchmarks reveal that unlike all‐atom docking, Q‐Dock^LHM exhibits the desired tolerance to the receptor's structure deformation. Our results suggest that the use of an evolution‐based approach to ligand homology modeling followed by fast low‐resolution refinement is capable of achieving satisfactory performance in ligand‐binding pose prediction with promising applicability to proteome‐scale applications. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2010     

Poly-intercalators Carrying Threading Intercalator Moieties as Novel DNA Targeting Ligands

Threading intercalators are a novel class of intercalators that carry two substituents along the diagonal positions of an aromatic ring. These substituents are projecting out in DNA grooves when bound to DNA. Poly-intercalators carrying threading intercalating parts are quite novel and were recently found to show a unique DNA binding behavior. We review herein two types of poly-intercalators. First, tris-intercalators carrying a threading intercalator part in the middle of the molecule are described. These intercalators appear to intercalate into double stranded DNA in a special binding manner, which we call the penetrating mode, in which all the three intercalating units are arranged linearly with one of them penetrating into the DNA ladder. We synthesized two tris-intercalators ( 3 and 4) of this type and studied their binding behavior for double stranded DNA. All the experimental results were consistent with the proposed penetrating mode. Another type of threading poly-intercalators is a macrocyclic bis-threading intercalator ( 5). We found that this compound can bis-intercalate to double stranded DNA when the base pairing is disrupted temporarily to form a complex with a unique structure like a catenane. On the basis of a study of the interaction of such intercalators we envisage that DNA is a flexible and dynamic entity. These novel families of poly-intercalators will expand the scope of DNA poly-intercalation chemistry with possible medicinal applications.     

Thread Insertion of a Bis(dipyridophenazine) Diruthenium Complex into the DNA Double Helix by the Extrusion of AT Base Pairs and Cross‐Linking of DNA Duplexes

The crystal structure of the Δ,Δ enantiomer of the binuclear “light‐switch” ruthenium complex [μ‐(11,11′‐bidppz)(1,10‐phenanthroline)₄ Ru₂]⁴⁺ bound to the oligonucleotide d(CGTACG) shows that one dppz moiety of the dumbbell‐like compound inserts into the DNA stack through the extrusion of an AT base pair. The second dppz moiety recruits a neighboring DNA molecule, and the complex thus cross‐links two adjacent duplexes by bridging their major grooves.     

Influence of double A1N buffer layers on the qualities of GaN films prepared by metal-organic chemical vapour deposition

<正>In this paper we report that the GaN thin film is grown by metal-organic chemical vapour deposition on a sapphire (0001) substrate with double AlN buffer layers.The buffer layer consists of a low-temperature(LT) AlN layer and a high-temperature(HT) AlN layer that are grown at 600℃and 1000℃,respectively.It is observed that the thickness of the LT-AlN layer drastically influences the quality of GaN thin film,and that the optimized 4.25-min-LT-AlN layer minimizes the dislocation density of GaN thin film.The reason for the improved properties is discussed in this paper.