Anti-aromatic compounds, as well as small cyclic alkynes or carbynes, are particularly challenging synthetic goals. The combination of their destabilizing features hinders attempts to prepare molecules such as pentalyne, an 8π-electron anti-aromatic bicycle with extremely high ring strain. Here we describe the facile synthesis of osmapentalyne derivatives that are thermally viable, despite containing the smallest angles observed so far at a carbyne carbon. The compounds are characterized using X-ray crystallography, and their computed energies and magnetic properties reveal aromatic character. Hence, the incorporation of the osmium centre not only reduces the ring strain of the parent pentalyne, but also converts its Hückel anti-aromaticity into Craig-type Möbius aromaticity in the metallapentalynes. The concept of aromaticity is thus extended to five-membered rings containing a metal-carbon triple bond. Moreover, these metal-aromatic compounds exhibit unusual optical effects such as near-infrared photoluminescence with particularly large Stokes shifts, long lifetimes and aggregation enhancement.

The direct transformation of cellulose, which is the main component of lignocellulosic biomass, into building-block chemicals is the key to establishing biomass-based sustainable chemical processes. Only limited successes have been achieved for such transformations under mild conditions. Here we report the simple and efficient chemocatalytic conversion of cellulose in water in the presence of dilute lead(II) ions, into lactic acid, which is a high-value chemical used for the production of fine chemicals and biodegradable plastics. The lactic acid yield from microcrystalline cellulose and several lignocellulose-based raw biomasses is 460% at 463 K. Both theoretical and experimental studies suggest that lead(II) in combination with water catalyses a series of cascading steps for lactic acid formation, including the isomerization of glucose formed via the hydrolysis of cellulose into fructose, the selective cleavage of the C3-C4 bond of fructose to trioses and the selective conversion of trioses into lactic acid.

Zinc-dependent histone deacetylase 8 (HDAC8) catalyzes the removal of acetyl moieties from histone tails, and is critically involved in regulating chromatin structure and gene expression. The detailed knowledge of its catalytic process is of high importance since it has been established as a most promising target for the development of new anti-tumor drugs. By employing BornOppenheimer ab initio QM/MM molecular dynamics simulations and umbrella sampling, a stateof-the-art approach to simulate enzyme reactions, we have provided further evidences against the originally proposed general acid-base catalytic pair mechanism for Zinc-dependent histone deacetylases. Instead, our results indicated that HDAC8 employs a proton-shuttle catalytic mechanism, in which a neutral His143 first serves as the general base to accept a proton from the zinc-bound water molecule in the initial rate-determining nucleophilic attack step, and then shuttles it to the amide nitrogen atom to facilitate the cleavage of the amide bond. During the deacetylation process, the Zn 2+ ion changes its coordination mode and plays multiple catalytic roles. For the K + ion, which is located about 7 Å from the catalytic Zn 2+ ion and conserved in class I and II HDACs, our simulations indicated that its removal would lead to the different transition state structure and a higher free energy reaction barrier for the rate-determining step. It is found that the existence of this conserved K + ion would enhance the substrate binding, increase the basicity of His143, strengthen the catalytic role of zinc ion and improve the transition state stabilization by the enzyme environment.

Molecular dynamics (MD) simulations have been performed at the atomic level to study the ammonium/ammonia transport across the Escherichia coli AmtB membrane protein. Although ammonia primarily exists in the form of NH(4)(+) in aqueous solution, the recent X-ray structure determination of AmtB reveals that the ammonium/ammonia transporter proteins are ammonia-conducting channels rather than ammonium ion transporters [Khademi, S.; et al. Science 2004, 305, 1587; Zheng, L.; et al. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 17090]. Our simulations showed that the entrance of NH(4)(+) into the periplasmic recruitment vestibule requires only 3.1 kcal/mol of energy. This is consistent with the X-ray crystal structure, where one NH(4)(+) is captured in the binding vestibule. In this vestibule, NH(4)(+) loses one water of hydration, but the loss is compensated by a hydrogen bond, first with the backbone carbonyl oxygen of Phe161 then with the hydroxyl group of Ser219, as well as the stabilizing pi-cation interactions with the aromatic rings of Trp148 and Phe107 in the AmtB protein. In the end of this recruitment vestibule, the phenyl ring of Phe107 dynamically switches to an open state. This is correlated with a slight rotation and shifting of the indole ring of Trp148, which eventually creates a slot for the initially buried carboxylate group of Asp160 to become exposed to the bulk solvent. A hydrogen bond wire between NH(4)(+) and the carboxylate group of Asp160 via two water molecules was observed. Thus, Asp160 is most likely the proton acceptor from NH(4)(+). This explains the high conservation of Asp160 in Amt proteins and why the D160A mutant would completely quench the activity of AmtB [Javelle, A.; et al. J. Biol. Chem. 2004, 279, 8530; Marini, A. M.; et al. Curr. Genet. 2006, 49, 364]. Once NH(4)(+) deprotonates, the phenyl ring of Phe215 rotates to open, and the subsequent passage of NH(3) through the channel is straightforward.

The interactions of nitrogen oxides NO(x) (x = 1,2,3) and N(2)O(4) with graphene and graphene oxides (GOs) were studied by the density functional theory. Optimized geometries, binding energies, and electronic structures of the gas molecule-adsorbed graphene and GO were determined on the basis of first-principles calculations. The adsorption of nitrogen oxides on GO is generally stronger than that on graphene due to the presence of the active defect sites, such as the hydroxyl and carbonyl functional groups and the carbon atom near these groups. These active defect sites increase the binding energies and enhance charge transfers from nitrogen oxides to GO, eventually leading to the chemisorption of gas molecules and the doping character transition from acceptor to donor for NO(2) and NO. The interaction of nitrogen oxides with GO with various functional groups can result in the formation of hydrogen bonds OH⋅⋅⋅O (N) between -OH and nitrogen oxides and new weak covalent bonds C⋅⋅⋅N and C⋅⋅⋅O, as well as the H abstraction to form nitrous acid- and nitric acidlike moieties. The spin-polarized density of states reveals a strong hybridization of frontier orbitals of NO(2) and NO(3) with the electronic states around the Fermi level of GO, and gives rise to the strong acceptor doping by these molecules and remarkable charge transfers from molecules to GO, compared to NO and N(2)O(4) adsorptions on GO. The calculated results show good agreement with experimental observations.

It is of significant biological interest and medical importance to develop class- and isoform-selective histone deacetylases (HDAC) modulators. The impact of the linker component on HDAC inhibition specificity was revealed, but has not been understood. Herein with Born-Oppenheimer ab initio QM/MM molecular dynamics simulations, a state-of-the-art approach to simulating metallo-enzymes, we have found that the hydroxamic acid remains to be protonated upon its binding to HDAC8, and thus disapproved the mechanistic hypothesis that the distinct zinc-hydroxamate chelation modes between two HDAC subclasses come from different protonation states of the hydroxamic acid. Instead, our simulations suggested a novel mechanism that the chelation mode of hydroxamate with the zinc ion in HDACs is modulated by water access to the linker binding channel. This new insight into the interplay between the linker binding and the zinc chelation emphasizes the importance and gives guidance regarding the linker design for the development of new class-IIa specific HDAC inhibitors.

AbstracsThe different coordination modes and fast ligand exchange of zinc coordination has been suggested to be one key catalytic feature of the zinc ion which makes it an invaluable metal in biological catalysis. However, partly due to the well known difficulties for zinc to be characterized by spectroscopy methods, evidence for dynamic nature of the catalytic zinc coordination has so far mainly been indirect. In this work, Born-Oppenheimer ab initio QM/MM molecular dynamics simulation has been employed, which allows for a first-principle description of the dynamics of the metal active site while properly including effects of the heterogeneous and fluctuating protein environment. Our simulations have provided direct evidence regarding inherent flexibility of the catalytic zinc coordination shell in Thermolysin (TLN) and Histone Deacetylase 8 (HDAC8). We have observed different coordination modes and fast ligand exchange during the picosecond's timescale. For TLN, the coordination of the carboxylate group of Glu166 to Zinc is found to continuously change between monodentate and bidentate manner dynamically; while for HDAC8, the flexibility mainly comes from the coordination to a non-amino-acid ligand. Such distinct dynamics in the zinc coordination shell between two enzymes suggests that the catalytic role of Zinc in TLN and HDAC8 is likely to be different in spite of the fact that both catalyze the hydrolysis of amide bond. Meanwhile, considering that such Born-Oppenheimer ab initio QM/MM MD simulations are very much desired but are widely considered to be too computationally expensive to be feasible, our current study demonstrates the viability and powerfulness of this state-of-the-art approach in simulating metalloenzymes.Zinc is relatively abundant in biological materials. Approximately 10% of the total human proteome have been identified to bind with zinc in vivo from a bioinformatics investigation1 and they play very crucial roles in all forms of life2 -6 . For mononuclear zinc enzymes, a typical metal coordination environment contains three amino acid side chain ligands (His, Glu, Asp and Cys) and one/two small molecule(s). 3, 7 , 8 The flexibility of zinc coordination, which allows different coordination modes and fast ligand exchange, has been suggested to be one key catalytic feature of the zinc ion which makes it an invaluable metal in biological catalysis.9 However, partly due to the well known difficulties for zinc to be characterized by spectroscopy methods 10,11 , evidence for dynamic nature of the catalytic zinc coordination has so far mainly In order to provide deep insights into the dynamics and flexibility of the zinc catalytic site, which would be essential in characterizing their catalytic mechanisms and rational design of novel inhibitors for zinc enzymes, we have carried out DFT QM/MM Born-Oppenheimer molecular dynamics (BOMD) simulations on TLN and HDAC8. Although semi-empirical QM/MM BOMD simulations of some zinc-dependent enzymes have been carried out 29-32, one main concern is the acc...

The interactions of ammonia with graphene oxides (GO) were studied by density functional theory calculations. Our results indicate that the adsorption of NH3 on GO is generally stronger than that on graphene because of the presence of diverse active defect sites, such as the hydroxyl and epoxy functional groups and their neighboring carbon atoms. These surface oxygen sites can form OH center dot center dot center dot N and O center dot center dot center dot HN hydrogen bonds with NH3 and enhance charge transfers from NH3 to the graphene oxide. The dissociation of the adsorbed NH3 into the chemisorbed NH2 or NH species through the H atom abstractions leads to hydroxyl group hydrogenation and ring-opening of epoxy group. The reactions of NH3 with the hydroxyl and epoxy groups are predicted to be exothermic with different energy barriers, depending on the oxidation species and the atomic arrangement of these groups. The hydroxyl group exhibits relatively higher reactivity toward hydrogen abstraction from the adsorbed NH3 than the epoxy group in GO with a single oxygen group. The presence of a neighboring OH group may activate the oxygen groups to facilitate the surface reaction of NH3. Followed by the ring-opening of the epoxy group, the newly formed hydroxyl group can be removed by the second H atom abstraction from NH2. The calculated density of states of the adsorbed systems also reveals strong interactions between GO and NH3. The calculated results show good agreement with available experimental observations.National Science Foundation of China [21103026, 21133007]; Ministry of Science and Technology [2011CB808504, 2012CB214900