Coupled folding-binding versus docking: a lattice model study

Using a simple hydrophobic/polar protein model, we perform a Monte Carlo study of the thermodynamics and kinetics of binding to a target structure for two closely related sequences, one of which has a unique folded state while the other is unstructured. We obtain significant differences in their binding behavior. The stable sequence has rigid docking as its preferred binding mode, while the unstructured chain tends to first attach to the target and then fold. The free-energy profiles associated with these two binding modes are compared.     

金属离子对HIV-1整合酶与硫氮硫扎平抑制剂作用模式影响的分子模拟研究

HIV-1整合酶（IN）通过依赖金属离子的两步反应将病毒DNA整合入宿主细胞过程中。结合于HIV-1上的金属离子个数的变化直接影响整合酶与抑制剂之间的结合。本工作用同源模建方法搭建了每条单链核心区具有两个Mg2+ 的（2Mg-IN-Core）和具有一个Mg2+ 的HIV-1 IN二聚体核心区模型（1Mg-IN-Core）。分子对接分别得到它们与硫氮硫扎平类化合物能量较低的复合物结构,把对接结果进行了比较。研究发现：当整合酶中结合的Mg2+个数改变时,它与抑制剂的结合模式也会发生很大的变化;抑制剂能够特异的且稳定的与2Mg-IN-Core模型的活性位点结合;同时与ASP64和GLU152螯合的那个Mg2+离子对于硫氮硫扎平抑制剂与整合酶上的结合有很大的影响。2Mg-IN-Core模型与抑制剂的复合物平均结构进行了2000 ps的 分子动力学模拟,分析发现同时与ASP64及ASP116螯合的Mg2+与IN蛋白形成了四个稳定的螯合键;同时与ASP64及GLU152螯合的Mg2+可与IN结合、也可与抑制剂形成稳定的配位键,这个Mg2+对IN与硫氮硫扎平抑制剂之间的结合有较大影响。     

Metal directed assembly of ditopic containers and their complexes with alkylammonium salts

A new self-folding cavitand has been assembled through metal coordination to give a thermodynamically stable ditopic receptor of nanosize dimensions which has been used in the reversible binding of di-alkylammonium and n-alkylammonium salts.     

Hydrogen-bonding interactions in acetic acid monohydrates and dihydrates by density-functional theory calculations

Equilibrium structures and the respective binding energies of acetic acid monohydrates and dihydrates have been determined by density-functional theory calculations with different basis sets, including 6-31+G(3d,p), 6-311++G(d,p), and 6-311++G(3df,3pd). Given that the C=O and OH groups in acetic acid provide the predominant hydrogen-bonding interactions with water, six stable conformer structures have been found each for the monohydrate and syn-dihydrate. Of the three syn- and three anti-conformers of acetic acid with water, the most stable monohydrate structure is found to be that of the syn-conformer bonding with water in a cyclic double H-bonded geometry. Similarly, the syn-conformer bonding with two water molecules in a cyclic double H-bonded geometry has also been determined to be the most stable among the six plausible structures for the syn-dihydrate. Frequency analysis of the stable conformers has been performed and the vibrational spectra of the most stable monohydrate and dihydrate structures are compared with the experimental gas-phase and matrix data. Furthermore, the calculated binding energies between an acetic acid and a water molecule for both monohydrate and dihydrate are larger than that between two water molecules, which supports our recent experimental observation of coevaporation of acetic acid with water upon annealing acetic acid on ice.     

PHOTOCHEMICALLY INDUCED BINDING OF Rh(phen)2Cl2+ TO DNA†

The photoinduced covalent binding of the title compound to native and heat denatured DNA is described. The level of binding has been measured by UV (for DNA) and atomic absorption (for Rh) analysis. Quantum efficiencies of 6.4 x 10(-4) mol Rh per mol photons and 1.6 x 10(-3) mol Rh per mol photons have been determined for binding to native and denatured calf thymus DNA, respectively. Levels of bound rhodium as high as 1 molecule per five bases have been achieved. There is no binding of the complex in the absence of light, and there is evidence that at least a portion of the binding may be due to the photolytic conversion of the complex into one or more stable intermediates. Studies with polyribonucleotides indicate a strong preference for binding to the purine bases.     

Theoretical Investigation on Binding Process of Allophanate to Allophanate Hydrolase

Several molecular simulation methods were integrated to investigate the detailed binding process of allophanate to allophanate hydrolase and predict their stable complex structure. The optimal enzyme-substrate complex conformation demonstrates that along with Arg307 and Tyr299, Gly124 is also one of the key anchor residues in the stable complex. The energetic calculation suggests the existence of an intermediate state in the enzyme-substrate binding process. The further atomic-level investigation illuminates that Tyr299, Arg307 and Ser172 can stabilize the substrate in the intermediate state. By this token, the residues Arg307 and Tyr299 function in both binding process and getting stable state.     

氯原子在Ag低指数面上的吸附位和吸附态

应用原子和表面簇合物相互作用的5参数Morse势方法(简称5-MP)对Cl-Ag低指数表面体系进行了研究, 并获得了全部的临界点特性, 如吸附位、吸附几何、结合能、正则振动等. 计算结果表明: 在Ag(100)面上, Cl原子吸附在四重洞位; 在Ag(111)面上, Cl吸附在三重洞位; 尽管第一与第二周期原子在(110)面上的稳定吸附态大都为赝式三重位和长桥位, 但在Ag(110)面上, 四重洞位是氯原子的稳定吸附态. 理论分析结果和实验推测结果符合得很好. 理论结果给出Cl原子在Ag表面的吸附结合能和表面簇合物的粗糙度有关, 结合能从小到大的顺序为(111)＜(100)＜(110).     

Cation binding effect on imidazole tautomerism

Binding of Zn²⁺ to imidazole (Im) and methyl imidazole (MeIm) is studied by ab initio methods as a model for the effect of cation binding on tautomeric energies. Gradient energy optimized conformations were obtained for all neutral and ionic structures, including the deprotonated molecules and the ylides. The N3? H tautomer of MeIm is calculated to be more stable than N1? H by about 1 kcal/mole. However, binding of a Zn²⁺ cation to the available nitrogen site is found to reverse the order of binding, leaving N1? H more stable by 1 kcal/mole. Binding of Zn²⁺ produces a significant perturbation in the electronic structure, a smaller shift in the equilibrium conformation of the imidazole ring, and only a small absolute shift in the relative tautomer energies. Methyl substitution at C5 has a small effect on both conformation and energetics. A high-energy ylide tautomer is produced by moving the proton bound to C2 to the N1 atom. The binding of Zn²⁺ to the C2 site is substantially stronger than to the N1 site, yielding nearly isoenergetic ZnIm²⁺ conformations for binding to either N or C atoms. For the deprotonated salts the lowest energy conformation has the C2? N3 bond bridged by Zn²⁺.     

[Nd(SSCNH2)4]-的电子结构 一种有机硫配位镧系络合物的模型阴离子

本文详细研究了络阴离子{Nd[SSCN(C_2H_5)_2]_4}~-的简化模型[Nd(SSCNH_2)_4]~-的电子结构和化学键合情况。从对键能的贡献看, 钕和硫原子之间的结合主要是离子性的, 但从电荷的重新分布看,应该认为共价结合对成键有一定贡献。σ键起主要作用, 对Nd—S和Nd—S′键来说, π键级只有σ键级的1/5～1/6。根据计算结果分析了为什么至今只合成了很少几种有机硫配位镧系络合物而存在大量稳定无机复合镧系硫化物的原因。建议了几种合成稳定的有机硫配位镧系络合物的可能途径。     

Synthesis of a new stable peristatic chiral pseudocryptand for simultaneous binding of boron and sodium

A new selective molecular receptor, borocryptate, based on the combination of the 15 membered ring diazatrioxa core and two saligenin units as binding sites for boron has been described. The resulting peristatic chiral compound is stable in air and easily converted to polynuclear complex, Na‐borocryptate, without using an inert atmosphere.     

Identification of the quinolinedione inhibitor binding site in Cdc25 phosphatase B through docking and molecular dynamics simulations

Cdc25 phosphatase B, a potential target for cancer therapy, is inhibited by a series of quinones. The binding site and mode of quinone inhibitors to Cdc25B remains unclear, whereas this information is important for structure-based drug design. We investigated the potential binding site of NSC663284 [DA3003-1 or 6-chloro-7-(2-morpholin-4-yl-ethylamino)-quinoline-5, 8-dione] through docking and molecular dynamics simulations. Of the two main binding sites suggested by docking, the molecular dynamics simulations only support one site for stable binding of the inhibitor. Binding sites in and near the Cdc25B catalytic site that have been suggested previously do not lead to stable binding in 50 ns molecular dynamics (MD) simulations. In contrast, a shallow pocket between the C-terminal helix and the catalytic site provides a favourable binding site that shows high stability. Two similar binding modes featuring protein-inhibitor interactions involving Tyr428, Arg482, Thr547 and Ser549 are identified by clustering analysis of all stable MD trajectories. The relatively flexible C-terminal region of Cdc25B contributes to inhibitor binding. The binding mode of NSC663284, identified through MD simulation, likely prevents the binding of protein substrates to Cdc25B. The present results provide useful information for the design of quinone inhibitors and their mechanism of inhibition.     

Zn2+'s ability to alter the distribution of Cu2+ among the available binding sites of Aβ(1-16)-polyethylenglycol-ylated peptide: implications in Alzheimer's disease

The formation of mixed copper(II) and zinc(II) complexes with Aβ(1-16)-PEG has been investigated. The peptide fragment forms stable mixed metal complexes at physiological pH in which the His13/His14 dyad is the zinc(II)'s preferred binding site, while copper(II) coordination occurs at the N-terminus also involving the His6 imidazole. Copper(II) is prevented by zinc(II) excess from the binding to the two His residues, His13 and His14. As the latter binding mode has been recently invoked to explain the redox activity of the copper-Aβ complex, the formation of ternary metal complexes may justify the recently proposed protective role of zinc(II) in Alzheimer's disease. Therefore, the reported results suggest that zinc(II) competes with copper for Aβ binding and inhibits copper-mediated Aβ redox chemistry.     

布洛芬与人血白蛋白位点II动态结合过程的分子模拟:一种结合途径分析

人血白蛋白（HSA）主要有两个药物结合位点,位点I和位点Ⅱ,许多小分子优先结合在位点Ⅱ上,包括抗炎类药物布洛芬。本文采用分子模拟方法研究了布洛芬小分子与HSA位点Ⅱ结合的动态过程,探讨了二者的结合机制。首先构建了50个随机分布的布洛芬与HSA复合物体系,经50 ns分子动力学模拟,其中一个布洛芬分子稳定结合于位点Ⅱ。基于该分子的运动轨迹分析,发现布洛芬的结合可分为四个阶段,即远程吸引、表面结合调整、进入位点Ⅱ空腔和稳定结合。比较范德华和静电相互作用能,发现初期以静电吸引为主,中期在HSA表面的两个极性区域间调整,逐步转移至位点Ⅱ附近;然后在位点Ⅱ入口处的极性残基和附近疏水残基的共同作用下,布洛芬进入位点Ⅱ空腔;进入空腔后,静电和疏水共同作用形成稳定结合。在结合过程中,位点Ⅱ附近的蛋白表面发生明显改变,体现出一定的“诱导契合”作用,同时分子模拟得到的结合模式和布洛芬-HSA结合的晶体结构类似。结果表明,分子模拟可以辅助研究小分子和蛋白结合的动态过程,从分子水平阐述相关结合机制。     

On the structure of the benzene-chlorine complex: a CNDO study

An oblique geometry in which the chlorine molecule is perpendicular to the benzene ring and centered over a carbon-carbon bond has been found to have a calculated CNDO binding energy more stable than those previously obtained for other geometrical models. This geometry is equivalent to the one preferred on the basis of infrared spectral studies of matrix-isolated benzene-chlorine complexes.     

A combined experimental and theoretical study of the molecular inclusion of organometallic sandwich complexes in a cavitand receptor

We describe herein a detailed study of the inclusion processes of several positively charged organometallic sandwich complexes inside the aromatic cavity of the self-folding octaamide cavitand 1. In all cases, the binding process produces aggregates with a simple 1:1 stoichiometry. The resulting inclusion complexes are not only thermodynamically stable, but also kinetically stable on the (1)H NMR spectroscopy timescale. The binding constants for the inclusion complexes were determined by different titration techniques. We have also investigated the kinetics of the binding process and the motion of the metallocenes included in the aromatic cavity of the host. Using DFT-based calculations, we have evaluated the energies of a diverse range of potential binding geometries for the complexes. We then computed the proton chemical shifts of the included guest in each one of the binding geometries. The agreement between the averaged computed values and the experimentally determined chemical shifts clearly supports the proposed binding geometries that we assigned to the inclusion complexes formed in solution. The combination of experimental and theoretical results has allowed us to elucidate the origins of the distinct features detected in the complexation process of the different guests, as well as their different motions inside the host.     

Many-body interaction in glycine-(water)3 complex using density functional theory method

Various configurations were investigated to find the most stable structures of glycine-(water)3 complex. Five different optimized conformers of glycine-(water)3 complex are obtained from density functional theory calculations using 6-311++G* basis set. Relaxation energy and many body interaction energies (two, three, and four body) are also calculated for these conformers. Out of the five conformers, the most stable conformer has the BSSE corrected total energy -513.917 967 7 Hartree and binding energy -27.28 Kcal/mol. It has been found that the relaxation energies, two body energies and three body energies have significant contribution to the total binding energy whereas four body energies are very small. The chemical hardness and chemical potential also confirmed the stability of the conformer having lowest total energy.     

Theoretical study of the adsorption of H on Si n clusters, (n=3-10)

A recently proposed local Fukui function is used to predict the binding site of atomic hydrogen on silicon clusters. To validate the predictions, an extensive search for the more stable SinH (n=3-10) clusters has been done using a modified genetic algorithm. In all cases, the isomer predicted by the Fukui function is found by the search, but it is not always the most stable one. It is discussed that in the cases where the geometrical structure of the bare silicon cluster suffers a considerable change due to the addition of one hydrogen atom, the situation is more complicated and the relaxation effects should be considered.     

Computational studies of Cu(II)/Met and Cu(I)/Met binding motifs relevant for the chemistry of Alzheimer's disease

A systematic study of the binding motifs of Cu(II) and Cu(I) to a methionine model peptide, namely, N-formylmethioninamide 1, has been carried out by quantum chemical computations. Geometries of the coordination modes obtained at the B3LYP/6-31G(d) level of theory are discussed in the context of copper coordination by the peptide backbone and the S atom of a methionine residue in peptides with special emphasis on Met35 of the amyloid-beta peptide (Abeta) of Alzheimer's disease. The relative binding free energies in the gas phase, DeltaG(g), are calculated at the B3LYP/6-311+G(2df,2p)//B3LYP/6-31G(d) level of theory, and the solvation affects are included by means of the COSMO model to obtain the relative binding energies in solution, DeltaG(aq). A free energy of binding, DeltaG(aq) = -19.4 kJ mol(-1), relative to aqueous Cu(II) and the free peptide is found for the most stable Cu(II)/Met complex, 12. The most stable Cu(I)/Met complex, 23, is bound by -15.6 kJ mol(-1) relative to the separated species. The reduction potential relative to the standard hydrogen electrode is estimated to be E degrees (12/23) = 0.41 V. On the basis of these results, the participation of Met35 as a low affinity binding site of Cu(II) in Abeta, and its role in the redox chemistry underlying Alzheimer's disease is discussed.     

Metal phosphonates applied to biotechnologies: a novel approach to oligonucleotide microarrays

A new process for preparing oligonucleotide arrays is described that uses surface grafting chemistry which is fundamentally different from the electrostatic adsorption and organic covalent binding methods normally employed. Solid supports are modified with a mixed organic/inorganic zirconium phosphonate monolayer film providing a stable, well-defined interface. Oligonucleotide probes terminated with phosphate are spotted directly on to the zirconated surface forming a covalent linkage. Specific binding of terminal phosphate groups with minimal binding of the internal phosphate diesters has been demonstrated. The mixed organic/inorganic thin films have also been extended for use arraying DNA duplex probes, and therefore represent a viable general approach to DNA-based bioarrays. Ideas for interfacing mixed organic/inorganic interfaces to other bioapplications are also discussed.     

A Novel Approach for the Evaluation of Positive Cooperative Guest Binding: Kinetic Consequences of Structural Tightening

Cooperativity is one of the most relevant features displayed by biomolecules. Thus, one of the challenges in the field of supramolecular chemistry is to understand the mechanisms underlying cooperative binding effects. Traditionally, cooperativity has been related to multivalent receptors, but Williams et al. have proposed a different interpretation based on the strengthening of noncovalent interactions within receptors upon binding. According to such an interpretation, positive cooperative binding operates through structural tightening. Hence, a quite counterintuitive kinetic behavior for positively cooperative bound complexes may be postulated: the more stable the complex, the slower it is formed. Such a hypothesis was tested in a synthetic system in which positive cooperative binding was previously confirmed by calorimetric experiments. Indeed, a linear correlation between the thermodynamics (ΔG°) and the kinetics (ΔG^≠) of guest binding confirmed the expected behavior. These distinctive kinetics provide solid evidence of positive cooperative guest binding, which is particularly useful bearing in mind that kinetic experiments are frequently and accurately carried out in both synthetic and biological systems.