Hydration of small peptides

The results for the sequential hydration of small peptides (<15 residues) obtained in our group are reviewed and put in perspective with other work published in the literature where appropriate. Our findings are based on hydration equilibrium measurements in a high-pressure drift cell inserted into an electrospray mass spectrometer and on calculations employing molecular mechanics and density functional theory methods. It is found that the ionic functional groups typically present in peptides, the ammonium, guanidinium, and carboxylate groups, are the primary target of water molecules binding to peptides. Whereas the water–guanidinium binding energy is fairly constant at 9 ± 1 kcal/mol, the water binding energy of an ammonium group ranges from 7 to 15 kcal/mol depending on how exposed the ammonium group is. A five-residue peptide containing an ammonium group is in favorable cases large enough to fully self-solvate the charge, but a pentapeptide containing a guanidinium group is too small to efficiently shield the charge of this much larger ionic group. The water–carboxylate interaction amounts to 13 kcal/mol with smaller values for a shielded carboxylate group. Both water bound to water in a second solvation shell and charge remote water molecules on the surface of the peptide are bound by 7–8 kcal/mol. The presence of several ionic groups in multiply charged peptides increases the number of favorable hydration sites, but does not enhance the water–peptide binding energy significantly. Water binding energies measured for the first four water molecules bound to protonated bradykinin do not show the declining trend typically observed for other peptides but are constant at 10 kcal/mol, a result consistent with a molecule containing a salt bridge with several good hydration sites. Questions regarding peptide structural changes as a function of number of solvating water molecules are discussed. Not much is known at present about the effect of individual water molecules on the conformation of peptides and on the stability of peptide zwitterions.     

Three dimensional model of severe acute respiratory syndrome coronavirus helicase ATPase catalytic domain and molecular design of severe acute respiratory syndrome coronavirus helicase inhibitors

The modeling of the severe acute respiratory syndrome coronavirus helicase ATPase catalytic domain was performed using the protein structure prediction Meta Server and the 3D Jury method for model selection, which resulted in the identification of 1JPR, 1UAA and 1W36 PDB structures as suitable templates for creating a full atom 3D model. This model was further utilized to design small molecules that are expected to block an ATPase catalytic pocket thus inhibit the enzymatic activity. Binding sites for various functional groups were identified in a series of molecular dynamics calculation. Their positions in the catalytic pocket were used as constraints in the Cambridge structural database search for molecules having the pharmacophores that interacted most strongly with the enzyme in a desired position. The subsequent MD simulations followed by calculations of binding energies of the designed molecules were compared to ATP identifying the most successful candidates, for likely inhibitors—molecules possessing two phosphonic acid moieties at distal ends of the molecule.     

新型π-扩展TTF衍生物的合成、晶体结构及量子化学计算

以对苯二胺为起始原料合成了2个新型的π-扩展四硫富瓦烯(TTF)衍生物,即N,N’-2(4,5-二苄硫基-1,3-二硫杂环戊烯-2-叶立德)-苯-1,4-二胺(5a)和N,N’-2(4,5-二甲酯基-1,3-二硫杂环戊烯-2-叶立德)-苯-1,4-二胺(5b),并利用氢核磁共振(1H NMR)、质谱(MS)、傅里叶变换红外光谱(FTIR)和单晶X射线衍射(XRD)等方法对化合物结构进行了表征.晶体结构分析结果表明,化合物5a和5b分属三斜晶系、P1空间群和单斜晶系、P21/n空间群.化合物5a和5b均为非平面结构分子,分子中对苯二亚胺平面和1,3-二硫杂环平面形成的二面角分别为87.61°(5a)和43.77°(5b).运用Gaussian 09程序,采用密度泛函理论(DFT)方法在B3LYP/6-31+G(d,p)水平上进行了量子化学计算,对化合物的前线分子轨道、静电势和电子吸收光谱进行了讨论,计算结果与实验值基本一致.     

Covalent binding of human serum albumin and ovalbumin by chloramine-T and chemical modification of the proteins

The covalent binding of ³⁵S-chloramine-T to human resum albumin (HSA) and ovalbumin is described. At pH 6.5, up to 24 chloramine-T molecules were found to be covalently bound per molecule of HSA; with ovalbumin the binding was only 5–7 molecule per protein molecule. Binding was accompanied by extensive modification of methionine, cysteine, histidine, tyrosine and lysine. Three new peaks appeared in the amino acid profiles of the modified proteins; two were identified as 1-aminoadipic acid (oxidation of lysine) and 3-chlorotyrosine. The most sites for covalent binding are lysine residues.     

Predicting the affinity of Farnesoid X Receptor ligands through a hierarchical ranking protocol: a D3R Grand Challenge 2 case study

The Drug Design Data Resource (D3R) Grand Challenges are blind contests organized to assess the state-of-the-art methods accuracy in predicting binding modes and relative binding free energies of experimentally validated ligands for a given target. The second stage of the D3R Grand Challenge 2 (GC2) was focused on ranking 102 compounds according to their predicted affinity for Farnesoid X Receptor. In this task, our workflow was ranked 5th out of the 77 submissions in the structure-based category. Our strategy consisted in (1) a combination of molecular docking using AutoDock 4.2 and manual edition of available structures for binding poses generation using SeeSAR, (2) the use of HYDE scoring for pose selection, and (3) a hierarchical ranking using HYDE and MM/GBSA. In this report, we detail our pose generation and ligands ranking protocols and provide guidelines to be used in a prospective computer aided drug design program.     

The Role of Packing,Dispersion, Electrostatics,and Solvation in High-Affinity Complexes of Cucurbit[n]urils with Uncharged Polar Guests

The rationalization of non-covalent binding trends is both of fundamental interest and provides new design concepts for biomimetic molecular systems. Cucurbit[n]urils (CBn) are known for a long time as the strongest synthetic binders for a wide range of (bio)organic compounds in water. However, their host-guest binding mechanism remains ambiguous despite their symmetric and simple macrocyclic structure and the wealth of literature reports. We herein report experimental thermodynamic binding parameters (ΔG, ΔH, TΔS) for CB7 and CB8 with a set of hydroxylated adamantanes, di-, and triamantanes as uncharged, rigid, and spherical/ellipsoidal guests. Binding geometries and binding energy decomposition were obtained from high-level theory computations. This study reveals that neither London dispersion interactions, nor electronic energies or entropic factors are decisive, selectivity-controlling factors for CBn complexes. In contrast, peculiar host-related solvation effects were identified as the major factor for rationalizing the unique behavior and record-affinity characteristics of cucurbit[n]urils.     

An anchor-dependent molecular docking process for docking small flexible molecules into rigid protein receptors

A molecular docking method designated as ADDock, anchor- dependent molecular docking process for docking small flexible molecules into rigid protein receptors, is presented in this article. ADDock makes the bond connection lists for atoms based on anchors chosen for building molecular structures for docking small flexible molecules or ligands into rigid active sites of protein receptors. ADDock employs an extended version of piecewise linear potential for scoring the docked structures. Since no translational motion for small molecules is implemented during the docking process, ADDock searches the best docking result by systematically changing the anchors chosen, which are usually the single-edge connected nodes or terminal hydrogen atoms of ligands. ADDock takes intact ligand structures generated during the docking process for computing the docked scores; therefore, no energy minimization is required in the evaluation phase of docking. The docking accuracy by ADDock for 92 receptor-ligand complexes docked is 91.3%. All these complexes have been docked by other groups using other docking methods. The receptor-ligand steric interaction energies computed by ADDock for some sets of active and inactive compounds selected and docked into the same receptor active sites are apparently separated. These results show that based on the steric interaction energies computed between the docked structures and receptor active sites, ADDock is able to separate active from inactive compounds for both being docked into the same receptor.     

Substantial improvements in large-scale redocking and screening using the novel HYDE scoring function

The HYDE scoring function consistently describes hydrogen bonding, the hydrophobic effect and desolvation. It relies on HYdration and DEsolvation terms which are calibrated using octanol/water partition coefficients of small molecules. We do not use affinity data for calibration, therefore HYDE is generally applicable to all protein targets. HYDE reflects the Gibbs free energy of binding while only considering the essential interactions of protein-ligand complexes. The greatest benefit of HYDE is that it yields a very intuitive atom-based score, which can be mapped onto the ligand and protein atoms. This allows the direct visualization of the score and consequently facilitates analysis of protein-ligand complexes during the lead optimization process. In this study, we validated our new scoring function by applying it in large-scale docking experiments. We could successfully predict the correct binding mode in 93% of complexes in redocking calculations on the Astex diverse set, while our performance in virtual screening experiments using the DUD dataset showed significant enrichment values with a mean AUC of 0.77 across all protein targets with little or no structural defects. As part of these studies, we also carried out a very detailed analysis of the data that revealed interesting pitfalls, which we highlight here and which should be addressed in future benchmark datasets.     

Poly(cyclic imino ether)s Beyond 2‐Substituted‐2‐oxazolines

2‐Oxazolines (2‐OZO) are 5‐membered cyclic imino ethers whose cationic ring‐opening polymerization (CROP) mechanism and resulting polymer properties are extensively studied. However, also 6‐ and 7‐membered cyclic imino ethers can be polymerized via CROP. Together with the much less studied 4‐ and 5‐substituted main‐chain chiral poly(2‐oxazoline)s (P‐2‐OZO), these compounds are interesting monomers to enhance the versatility of (co)poly(cyclic imino ether)s. To emphasize the potential of such alternative cyclic imino ether monomers, we provide an overview on the polymerizations of 2‐oxazine (2‐OZI) and chiral 4‐ and 5‐substituted 2‐OZO as well as of selected properties of the resulting polymers. In addition, the hydrolysis of these polymers into the corresponding poly(alkylene imine)s will be addressed.

     

Structural Basis for Recognition of Guanosine by a Synthetic Tricyclic Cytosine Analogue: Guanidinium G‐Clamp

An oligonucleotide analogue containing a novel heterocyclic analogue, the guanidinium G‐clamp, was designed to allow formation of five H‐bonds to guanosine. The guanidinium group was introduced postsynthetically by treatment of the deprotected oligonucleotide containing a free amino group with a solution of 1H‐pyrazole‐1‐carboxamidine and purified by a combination of size‐exclusion chromatography and reversed‐phase HPLC. A single incorporation of this modification into an oligodeoxynucleotide sequence was found to increase duplex stability by 13° and 16° per modification to RNA and DNA, respectively. Crystals of a self‐complementary decamer sequence containing this modification were grown and diffracted to 1‐Å resolution. The structure was solved by molecular replacement and revealed that the modification forms additional H‐bonds to O(6) and N(7) of guanosine through the amino and imino N‐atoms, respectively. The origins of enhanced duplex stability are also attributed to increased stacking interactions mediated by the phenoxazine moiety of the G‐clamp and formation of H‐bond networks between the positively charged guanidinium group, H₂O molecules, and negatively charged O‐atoms from phosphates on the adjacent strand.     

Potential energy surfaces for oxygen adsorption, dissociation, and diffusion at the Pt(321) surface

We report a first-principles, periodic supercell analysis of oxygen adsorption, diffusion, and dissociation at the kinked Pt(321) surface. Binding energies and binding site preferences of isolated oxygen atoms and molecules have been determined, and we show that both atomic and molecular oxygen prefer binding in bridge sites involving coordinatively unsaturated kink Pt atoms. Binding energies of atomic and molecular oxygen in different sites correlate well with the average metallic Pt coordination number of Pt atoms forming each site, although differences exist between adsorbates in symmetrically similar sites due to the inherent chirality of the surface. Atomic O in the strongest binding bridge sites experiences relatively small energy barriers for diffusion to neighboring sites compared to O on Pt(111). However, due to the structure of the surface, O diffusion is only rapid between different sites around the kink Pt atom, whereas the effective long-range tracer diffusion, as determined from a simple course-grain model, is shown to be anisotropic and slower than on the Pt(111) surface. Four dissociation pathways for O(2) at low coverage are also reported and found to be in agreement with experimental observations of facile dissociation, even at low temperature.     

A Cu(II) Complex with IM-MeImz-κ~2 N,O Mode in [Cu(IM-MeImz)_2]·(SCN)_2: Synthesis, Crystal Structure and Magnetic Properties

A new copper(II) compound with imino nitroxide radicals [Cu(IM-MeImz)2]?(SCN)2 (IM-meImz =2-(5-methylimidazol-4-yl)-4,4,5,5-tetramethyl-2-imidazoline-1-oxyl) has been synthesized and characterized structurally and magnetically. It crystallizes in monoclinic, space group P21/c with a = 9.3604(7), b = 10.3012(7), c = 16.6684(12) , β = 105.0290(10)o, V = 1552.25(19) 3, C24H34CuN10O2S2, Mr = 622.27, Z = 2, Dc = 1.331 g/cm3, μ(MoKα) = 0.876 mm-1, F(000) = 650, the final R = 0.0374 and wR = 0.1079. X-ray analysis demonstrates that the IM-MeImz ligand is coordinated to the copper(II) ion as an unusual didentate chelate with a κ2 N(MeImz),O(IM) mode in the complex. The square-planar coordination sites at Cu(II) are occupied by two O and two N atoms from the imino nitroxide radicals. The complex molecules are connected as a onedimensional polymer structure by intermolecular interactions. Magnetic measurements show that there are intramolecular antiferromagnetic interactions between the Cu(II) ion and radicals.     

A Cu(Ⅱ) Complex with IM-MeImz-к2 N,O Mode in [Cu(IM-MeImz)2]·(SCN)2: Synthesis, Crystal Structure and Magnetic Properties

A new copper(Ⅱ) compound with imino nitroxide radicals [Cu(IM-MeImz)2]·(SCN)2 (IM-meImz =2-(5-methylimidazol-4-yl)-4,4,5,5-tetramethyl-2-imidazoline-1-oxyl) has been synthesized and characterized structurally and magnetically. It crystallizes in monoclinic, space group P21/c with a = 9.3604(7), b = 10.3012(7), c = 16.6684(12) (A), β = 105.0290(10)°, V = 1552.25(19)(A)3, C24H34CuN10O2S2, Mr = 622.27, Z = 2, Dc = 1.331 g/cm3, μ(MoKα) = 0.876 mm-1, F(000) =650, the final R = 0.0374 and wR = 0.1079. X-ray analysis demonstrates that the IM-MeImz ligand is coordinated to the copper(Ⅱ) ion as an unusual didentate chelate with a κ2 N(MeImz),O(IM) mode in the complex. The square-planar coordination sites at Cu(Ⅱ) are occupied by two O and two N atoms from the imino nitroxide radicals. The complex molecules are connected as a onedimensional polymer structure by intermolecular interactions. Magnetic measurements show that there are intramolecular antiferromagnetic interactions between the Cu(Ⅱ) ion and radicals.     

Synthesis and antidiabetic activity of novel triazole derivatives containing amino acids

New series of triazole derivatives coupled with amino acids 1a-h were obtained via multicomponent reaction of 2-hydroxy benzaldehyde or 2-hydroxy acetophenone with thiosemicarbazide and different amino acids. The obtained compounds were reacted with p-toluinesulfonyl chloride 2 to give the corresponding sulfonamides 3a-h . Compound 1b was allowed to react with different aromatic aldehydes or cyclic ketone under alkaline conditions to afford the expected imino compounds 4a-d and 6a-c , respectively. These compounds were allowed to react with ethyl glycolate to yield the expected thiazolidinone derivatives 5a-d or 7a-c , respectively. Structures of the newly synthesized compounds were found to be in accordance with their elemental analyses and spectral data. The obtained compounds exhibited very prominent in vitro and in vivo antihyperglycemic effect at a dose of 40 mg/kg body weight compared to the standard drug gliclazide and control. The antidiabetic effect was investigated using oral glucose tolerance test in normal and non-insulin-dependent diabetes mellitus (NIDDM) in STZ-rat model. Compounds 3a - h , 5b , 5c , 5d , 7a , 7b , and 7c showed significant activity in lowering blood glucose (more than 80%) compared to the NIDDM control.     

Regarding the effect that different hydrocarbon/fluorocarbon surfactant mixtures have on their complexation with HSA

The complexations between human serum albumin (HSA) and the sodium perfluorooctanoate/sodium octanoate and sodium perfluorooctanoate/sodium dodecanoate systems have been studied by a combination of electrical conductivity, ion-selective electrode, electrophoresis, and spectroscopy measurements. The binary mixtures of the surfactants deviated slightly from ideality. Binding plots revealed the existence of two specific binding sites, the first site being more accessible than the second. Positive cooperative binding has been found, thus revealing the importance of the hydrophobic interactions in both kinds of surfactants. The Gibbs energies of binding per mole of surfactant (DeltaG(nu)) were calculated from the Wyman binding potential where, on the basis of the elevated number of binding sites, a statistical contribution has been included. Initially these energies are large and negative, gradually decreasing as saturation is approached. Changes in the slope of Gibbs energies have been identified with the saturation of the first binding set. These facts denote that the surfactants under study have different favorite adsorption sites along the protein and that the adsorption process of perfluorooctanoate is more closely followed by dodecanoate than by octanoate. Finally, electrophoresis and spectroscopy measurements suggest induced conformational changes on HSA depending on the surfactant mixture as well as the mixed ratio.     

Binding energies of first row diatomics in the light of the interacting quantum atoms approach

Binding energies of first row diatomics are revisited within the interacting quantum atoms (IQA) approach. This is a formalism in chemical bonding theory based upon the quantum theory of atoms in molecules. It is characterized by the preservation of the energetic identity of atoms within molecules. Quantum mechanically computed binding energies are recovered in IQA as a sum of small atomic deformation energies and large pairwise interaction terms. We show how this partition responds faithfully to chemical intuition, and how the different evolution of deformations and interactions accounts in a unified manner for the subtle variations of the binding energy of these molecules.     

Metal-free catalysts for the hydrolysis of RNA derived from guanidines, 2-aminopyridines, and 2-aminobenzimidazoles

2-aminopyridine and 2-aminobenzimidazole were chosen as structural analogues to substitute guanidinium groups in receptor molecules designed as phosphoryl transfer catalysts. Shifting the pKa of the guanidinium analogues toward 7 was expected to raise catalytic activities in aqueous buffer. Although the pKa's of both heterocycles are similar (6.2 and 7.0), only 2-aminobenzimidazole led to active RNA cleavers. All cleavage assays were run with fluorescently labeled substrates and a DNA sequencer. RNase contaminations would degrade RNA enantioselectively. In contrast, achiral catalysts such as 9b and 10b necessarily induce identical cleavage patterns in RNA and its mirror image. This principle allowed us to safely rule out contamination effects in this study. The most active catalysts, tris(2-aminobenzimidazoles) 9b and 10b, were shown by fluorescence correlation spectroscopy (FCS) to aggregate with oligonucleotides. However, at very low concentrations the compounds are still active in the nonaggregated state. Conjugates of 10b with antisense oligonucleotides or RNA binding peptides, therefore, will be promising candidates as site specific artificial ribonucleases.     

用密度泛函理论研究NO在H-ZSM-5分子筛不同酸性位的吸附

利用密度泛函理论(DFT),基于7T簇模型,在B3LYP/6-31G(d,p)水平上研究了NO分子在H-ZSM-5分子筛孔道中α,β,γ酸性位的吸附.在计算过程中,首先对H-ZSM-5的α,β,γ酸性位进行优化计算,然后对NO分子η1-N和η1-O两种吸附模式的红外光谱和吸附能进行计算.计算结果表明,NO分子以η1-N模式吸附于H-ZSM-5分子筛酸性位上,不同酸性位对NO分子的吸附能力排序为:α酸性位>β酸性位>γ酸性位.此外,H-ZSM-5分子筛直型孔道更有利于NO分子的吸附和扩散,因而可更有效地促进NO分子催化分解反应的进行.     

Carbodicarbenes and Related Divalent Carbon(0) Compounds

Quantum‐chemical calculations using DFT and ab initio methods have been carried out for fourteen divalent carbon(0) compounds (carbones), in which the bonding situation at the two‐coordinate carbon atom can be described in terms of donor–acceptor interactions L→C←L. The charge‐ and energy‐decomposition analysis of the electronic structure of compounds 1 – 10 reveals divalent carbon(0) character in different degrees for all molecules. Carbone‐type bonding L→C←L is particularly strong for the carbodicarbenes 1 and 2 , for the “bent allenes” 3 a , 3 b , 4 a , and 4 b , and for the carbocarbenephosphoranes 7 a , 7 b , and 7 c . The last‐named molecules have very large first and large second proton affinities. They also bind two BH₃ ligands with very high bond energies, which are large enough that the bis‐adducts should be isolable in a condensed phase. The second proton affinities of the complexes 5 , 6 , and 8 – 10 bearing CO or N₂ as ligand are significantly lower than those of the other molecules. However, they give stable complexes with two BH₃ ligands and thus are twofold Lewis bases. The calculated data thus identify 1 – 10 as carbones L→C←L in which the carbon atom has two electron pairs. The chemistry of carbones is different from that of carbenes because divalent carbon(0) compounds CL₂ are π donors and thus may serve as double Lewis bases, while divalent carbon(II) compounds are π acceptors. The theoretical results point toward new directions for experimental research in the field of low‐coordinate carbon compounds.