Giuseppe D. Ruggiero

Computational mutagenesis reveals the role of active-site tyrosine in stabilising a boat conformation for the substrate: QM/MM molecular dynamics studies of wild-type and mutant xylanases

Molecular dynamics simulations have been performed for non-covalent complexes of phenyl beta-xylobioside with the retaining endo-beta-1,4-xylanase from B. circulans (BCX) and its Tyr69Phe mutant using a hybrid QM/MM methodology. A trajectory initiated for the wild-type enzyme-substrate complex with the proximal xylose ring bound at the -1 subsite (adjacent to the scissile glycosidic bond) in the (4)C(1) chair conformation shows spontaneous transformation to the (2,5)B boat conformation, and potential of mean force calculations indicate that the boat is approximately 30 kJ mol(-1) lower in free energy than the chair. Analogous simulations for the mutant lacking one oxygen atom confirm the key role of Tyr69 in stabilizing the boat in preference to the (4)C(1) chair conformation, with a relative free energy difference of about 20 kJ mol(-1), by donating a hydrogen bond to the endocyclic oxygen of the proximal xylose ring. QM/MM MD simulations for phenyl beta-xyloside in water, with and without a propionate/propionic acid pair to mimic the catalytic glutamate/glutamic acid pair of the enzyme, show the (4)C(1) chair to be stable, although a hydrogen bond between the OH group at C2 of xylose and the propionate moiety seems to provide some stabilization for the (2,5)B conformation.

[(PPh3)Ag(HCB11Me11)]: A Complex with Intermolecular Ag⋅⋅⋅H3C Interactions

Both in the solid state and in solution, the complex [(PPh3)Ag(HCB11Me11)] displays significant intermolecular Ag⋅⋅⋅H3C interactions. This complex serves as a model for the interaction between a d10 metal center and an alkane.

A hybrid quantum mechanical molecular mechanical method: Application to hydration free energy calculations

A hybrid quantum mechanical molecular mechanical (QMMM) approach is used to study H3O+, H2O, NH4+, NH3, Cl−, HCl, F−, HF, CH3COO−, CH3COOH, Ag+ and glycine in both zwitterionic and nonzwitterionic forms in water. The free energies of hydration of these species are presented and are shown to compare favorably with experimental values. The difference in water–glycine interaction energy between the zwitterionic and nonzwitterionic forms is calculated as a lower limit and is in line with previous findings. The first theoretical examination of the Ag+–glycine complex in solution is presented.

Dyotropic rearrangement of alpha-lactone to beta-lactone: a computational study of small-ring halolactonisation

Transition structures have been optimised using the B3LYP/6-31+G* density functional level method, in vacuum and in implicit (PCM) and explicit (DFT/MM) aqueous solvation, for the degenerate rearrangement of the alpha-lactone derived by the formal addition of Cl(+) to acrylate anion and for the dyotropic rearrangement of this to the beta-lactone. Despite being lower in energy than the alpha-lactone, there is no direct pathway to the beta-lactone from the acrylate chloronium zwitterion, which is the transition structure for the degenerate rearrangement. This may be rationalised by consideration of the unfavorable angle of attack by the carboxylate nucleophile on the beta-position; attack on the alpha-position involves a less unfavorable angle. Formation of the beta-lactone may occur by means of a dyotropic rearrangement of the alpha-lactone. This involves a high energy barrier for the acrylate derived alpha-lactone, but dyotropic rearrangement of the beta,beta-dimethyl substituted alpha-lactone to the corresponding beta-lactone involves a much lower barrier, estimated at about 46 kJ mol(-1) in water, and is predicted to be a facile process.

exo-closo-Rhodacarboranes: synthesis and characterisation of [{exo-(R3P)2Rh}(closo-CB11H12)] [R3P=P(OMe)3, PCy3, 1/2dppe]

Abstract Addition of H2 to CH2Cl2 solutions of [(diene)Rh(L)2][closo-CB11H12] (diene=norbornadiene, cyclooctadiene, L=PCy3, P(OMe)3, 1/2dppe) results in the formation of the exo-closo complexes [(PR3)2Rh(closo-CB11H12)]. These have been characterised in solution by 1H- and 11B-NMR spectroscopy, and for L=PCy3 by a single crystal X-ray diffraction study. This suggests that the metal fragment is bound with the cage through the 7,8- and not the 7,12-{BH} vertices. DFT calculations on a model system where L=PMe3 show that there is only a negligible energy difference between these two isomers (1 kcal mol−1), suggesting that both represent stable structures. The salient spectroscopic markers that indicate an interaction of [closo-CB11H12]− with a metal fragment are discussed and compared across a range of metal complexes. Large upfield shifts in the 11B-NMR spectrum and a small downfield shift of the CH vertex in the 1H-NMR spectrum are shown to the most reliable indicators of borane interaction in solution.

Computational Investigation of Mechanisms for Ring-Opening Polymerization of ε-Caprolactone: Evidence for Bifunctional Catalysis by Alcohols.

Stepwise addition/elimination and concerted mechanisms for the methanolysis of ε-caprolactone, as a model for the initiation and propagation of ring-opening polymerization (ROP), have been investigated computationally using the B3LYP/6-31G* density functional method, with assistance from one or two ancillary methanol molecules. The effects of specific solvation by these extra methanols in cyclic hydrogen-bonded clusters are very significant, with barrier height reductions of about 50 kJ mol(-)(1). However, the effects of bulk solvation as treated by the polarized continuum model are almost negligible. Increasing the ring size lowers the barriers for both the addition and elimination steps of the stepwise mechanism but does not do so for the concerted mechanism; a stepwise mechanism is preferred for methanol-assisted ROP. The essential catalytic role of solvent molecules in this reaction is to avoid the unfavorable accumulation or separation of charges.

Kinetic isotope effects for gas phase SN2 methyl transfer: a computational study of anionic and cationic identity reactions

The relationship between energy barriers, transition-state looseness and 2° α-deuterium kinetic isotope effects (KIEs) has been re-evaluated for a range of identity SN2 methyl transfer reactions that extends to “exploded” transition structures (TSs). Ab initio MP2/6-311+G* molecular orbital calculations have been performed for reactions involving the neutral nucleophiles X = CO, N2, NH3, N(CH3)3, OH2, Kr, Ar, Ne and He, along with anionic nucleophiles X− = F, Cl, Br, CN, NC, CCH, and OH. The behaviour previously noted by Wolfe and co-workers, from MP2/6-31+G* studies of identity and non-identity methyl transfers with anionic nucleophiles and neutral electrophiles only, does not apply to the broader range which also includes neutral nucleophiles and cationic electrophiles: a looser TS is not associated with a higher energy barrier and a more inverse 2° α-D KIE. Moreover, when the interaction of the nucleophile with the electrophile in the reactant complex (RC) is considered, no simple relationships between “looseness” or “tightness” and either energy barriers or KIEs are found. The variation in energy barriers may be understood by means of a simple model involving the distance travelled by the methyl group within the encounter complex from RC to the product complex (PC) and the force constant for stretching the bond to the leaving group in RC. There is a fair linear correlation between the 2° α-D KIE and the change in this same stretching force constant, from RC to TS. The methyl group in the SN2 TS does not resemble an isolated methyl cation, even for systems showing “SN1-like” properties, owing to the significant influence of the nucleophile and leaving group. Consideration of the unusual range of nucleophiles X = Kr, Ar, Ne and He in identity reactions with CH3X+ shows a mechanistic changeover from a double-well potential with a true SN2 TS to a single-well potential with a symmetric intermediate corresponding to a solvated methyl cation.

Oxiranones: α-lactones or zwitterions? Insights from calculated electron density distribution analysis

Electron density distributions for oxiranone and hydroxyoxiranone have been analysed in vacuo [MP2/6-31+G(d,p)] and in water [SCI-PCM/MP2/6-31+G(d,p)//HF/6-31+G(d,p)] and compared with those for cyclopropane, cyclopropanone, and oxirane. Oxiranone possesses a ring critical point in vacuo, and may be considered as an α-lactone with considerable ionic character in the endocyclic Cα–On bond. In water, oxiranone has neither a ring critical point nor a bond critical point for Cα–On, and may be considered as a zwitterion, whose carboxylate group has a net charge of −0.63. Geometrically, however, the molecule still possesses an acute-angled three-membered ring with a CαCOn angle of only 69°. Electronically, hydroxyoxiranone is acyclic and zwitterionic even in vacuo, but geometrically it still looks like an α-lactone.

The Walden cycle revisited: a computational study of competitive ring closure to α- and β-lactones

The text-book Walden cycle which interconverts the stereochemical configurations of chlorosuccinic and malic acids involves a β-lactone intermediate in preference to an α-lactone intermediate because the Onuc C Cl angle in the transition structure for the former (174°) is more favourable than that for the latter (139°), as determined by PCM(e = 78.4)/B3LYP/6-31+G* calculations; the smaller ring-strain energy of the β-lactone contributes little to the reactivity difference.

Well-defined indium(iii) N-heterocyclic carbene complexes with triflate ligands: Structural models for the In(OTf)3 catalystElectronic supplementary information (ESI) available: Full experimental data for the new compounds. See http://www.rsc.org/suppdata/dt/b4/b404179h/

Reaction of 1,3-dimesitylimidazolium chloride [IMesH]Cl with InMe3 results in (IMes)InMe2Cl, which on treatment with one equivalent of TMS-OTf affords (IMes)InMe2(OTf), which can be converted to the bistriflate complex (IMes)In(Me)(OTf)2 on addition of HOTf.