Linkage Isomers of Triangular Pd Metallacycles and Catalysis in Aqueous Suzuki Coupling Reaction.

The water-soluble trinuclear Pd metallacycles [Pd(tmeda)(4-Spy)]3(X)3 (tmeda = tetramethylethylenediamine, X = OTf, 2; NO3, 3) were synthesized from the ambidentate ligand 4-pyridylthiolate (Spy-) and [Pd(tmeda)X2] in 80 and 70% yield, respectively. Two possible linkage isomers are found in solution (slow interconversion found in the NMR) and in the solid state. Density functional calculations showed that the energy of the isomer with a D3-symmetric arrangement of the SPy ligand and all Pd atoms having N∧NPdSN coordination is only 7 kcal/mol lower. When reacting [Pd(tmeda)(NO3)2] with 4,4'-biphenyldithiolate (S2bph2-), the tetranuclear [{Pd(tmeda)}4(µ-S2bph)2](NO3)4 (1) was formed. A new type of undecanuclear Pd cluster was separated as a minor product from an acetone solution of 2 in air. The new complexes represent the first examples of water-soluble Pd metallacycles constructed from a pyridine-thiolate ligand. They show catalytic activity with turnover numbers ranging from 9 to 420 in aqueous Suzuki cross-coupling reactions using phenyl boronic acid and a number of aryl halides. An optimized system gave a TON of 6,900,000 and a TOF of 492,857 h-1. The catalyst could be reused eight times, and the activity has been attributed to the formation of PdNPs.

Binding of human serum albumin with uranyl ion at various pH: an all atom molecular dynamics study.

Uranium is routinely handled in various stages of nuclear fuel cycle and its association with human serum albumin (HSA) has been reported in literature, however, their binding characteristics still remains obscure. The present study aims to understand interaction of uranium with HSA by employing all atom molecular dynamics simulation of the HSA-metal ion complex. His67, His247 and Asp249 residues constitute the major binding site of HSA, which capture the uranyl ion (UO22+). A total of six sets of initial coordinates are used for Zn2+-HSA and UO22+-HSA system at pH = 4, 7.4 and 9, respectively. Enhance sampling method, namely, well-tempered meta-dynamics (WT-MtD) is employed to study the binding and un-binding processes of UO22+ and Zn2+ ions. Potential of mean force (PMF) profiles are generated for all the six sets of complexes from the converged WT-MtD run. Various basins and barriers are observed along the (un)binding pathways. Hydrogen bond dynamics and short-range Coulomb interactions are evaluated from the equilibrium run at each basins and barriers for both the ions at all pH values. The binding of UO22+ ion with HSA is the result of the dynamical balance between UO22+-HSA and UO22+-water short range Coulomb interactions. Zn2+ ion interact more strongly than UO22+ at all pH through short range Coulomb interactions. PMF values further concludes that UO22+ cannot associate to the Zn2+ bound HSA protein but can be captured by free HSA at all pH values i.e. endosomal, alkaline and physiological pH.Communicated by Ramaswamy H. Sarma.

Heat-induced transitions of an empty minute virus of mice capsid in explicit water: all-atom MD simulation.

The capsid-like structure of the virus-based protein nanoparticles (NPs) can serve as bionanomaterials, with applications in biomedicines and nanotechnology. Release of packaged material from these nanocontainers is associated with subtle conformational changes of the NP structure, which in vitro, is readily accomplished by heating. Characterizing the structural changes as a function of temperature may provide fresh insights into nanomaterial/antiviral strategies. Here, we have calculated heat induced changes in the properties of an empty minute virus of mice particle using large-scale ≈ 3.0 × 106 all-atom molecular dynamics simulations. We focus on two heat induced structural changes of the NP, namely, dynamical transition (DT) and breathing transition (BT), both characterized by sudden and sharp change of measured parameters at temperatures, TDT and TBT, respectively. While DT is assessed by mean-square fluctuation of hydrogen atoms of the NP, BT is monitored through internal volume and permeation rate of water molecules through the NP. Both the transitions, resulting primarily from collective atomistic motion, are found to occur at temperatures widely separated from one another (TBT>TDT). The breathing motions, responsible for the translocation events of the packaged materials through the NP to kick off, are further probed by computing atomic resolution stresses from NVE simulations. Distribution of equilibrium atomistic stresses on the NP reveals a largely asymmetric nature and suggests structural breathing may actually represent large dynamic changes in the hotspot regions, far from the NP pores, which is in remarkable resemblance with recently conducted hydrogen-deuterium exchange coupled to mass spectrometry experiment. Communicated by Ramaswamy H. Sarma.

Temperature Induced Dynamical Transition of Biomolecules in Polarizable and Nonpolarizable TIP3P Water.

Temperature induced dynamical transition (DT), associated with a sharp rise in molecular flexibility, is well-known to be exhibited between 270 and 280 K in glycerol to 200-230 K in hydrated biomolecules and is controlled by diffusivity (viscosity) of the solvation layer. In the molecular dynamics (MD) community, especially for water as a solvent, this has been an intense area of research despite decades of investigations. However, in general, water in these studies is described by empirical nonpolarizable force fields in which electronic polarizability is treated implicitly with effective charges and related parameters. This might have led to the present trait of discovery that DTs of biomolecules, irrespective of the potential functions for water models used, occur within a narrow band of temperature variation (30-40 K). Whereas a water molecule in a biomolecular surface and one in bulk are polarized differently, therefore explicit treatment of water polarizability would be a powerful approach toward the treatment of hydration water, believed to cause the DT manifestation. Using MD simulations, we investigated the effects of polarizable water on the DT of biomolecules and the dynamic properties of hydration water. We chose two types of solutes: globular protein (lysozyme) and more open and flexible RNAs (a hairpin and a riboswitch) with different natures of hydrophilic sites than proteins in general. We found that the characteristic temperature of DT ( TDT) for the solutes in polarizable water is always higher than that in its nonpolarizable counterpart. In particular, for RNAs, the variations are found to be ∼45 K between the two water models, whereas for the more compact lysozyme, it is only ∼4 K. The results are discussed in light of the enormous increase in relaxation times of a liquid upon cooling in the paradigm of dynamic switchover in hydration water with liquid-liquid phase transition, derived from the existence of the second critical point. Our result supports the idea that structures of biomolecules and their interactions with the hydration water determines TDT and provides evidence for the decisive role of polarizable water on the onset of DT, which has been hitherto ignored.

Xantphos-Capped Pd(II) and Pt(II) Macrocycles of Aryldithiolates: Structural Variation and Catalysis in C-C Coupling Reaction.

The self-assembly of Xantphos-capped M(OTf)2 (M = cis-[M'(Xantphos)]2+; M' = Pd, Pt) with bridging ligands 1,4-benezenedithiol or 4,4'-biphenyldithiol has been investigated. The reactions have yielded complexes [M{S(C6H4) nSH}]2(OTf)2 (I) and [M2{S(C6H4) nS}]2(OTf)4 (II) ( n = 1 or 2). The equilibrium between I and II has been established in platinum complexes for n = 2, whereas the analogous Pd complex exclusively exist as II. These results are different from our previously reported dppe or triethyl phosphine-capped complexes which showed only type II. The same reaction with 1,3-benezenedithiol lead to the complex [M2(SC6H4SSC6H4S)](OTf)2 (III), containing a S-S bond between two thiolate ligands, formed via a complex of type I in solution. Characterization of the complexes was accomplished by NMR spectroscopy, UV-vis spectroscopy and mass spectrometry, and X-ray crystallography. Density functional calculations were performed to estimate the relative stability of three types of complexes. The palladium complexes are excellent catalysts in Suzuki C-C cross coupling reactions under mild conditions, and can be reused eight times without losing significant yield. The activity of the Pd catalysts derived from three dithiol ligand follows opposite trend of the stability as III > II > I. The comparative catalytic activity of the tetranuclear Pd complexes (II) of bis-phosphines of varied bite angles, including the structurally characterized [Pd2(dppf)2(SC12H8S)]2(OTf)4 has also been demonstrated.

Effect of pH on the hinge region of influenza viral protein: a combined constant pH and well-tempered molecular dynamics study.

Despite the knowledge that the influenza protein, hemagglutinin, undergoes a large conformational change at low pH during the process of fusion with the host cell, its molecular mechanism remains elusive. The present constant pH molecular dynamics (CpHMD) study identifies the residues responsible for large conformational change in acidic condition. Based on the pKa calculations, it is predicted that His-106 is much more responsible for the large conformational change than any other residues in the hinge region of hemagglutinin protein. Potential of mean force profile from well-tempered meta-dynamics (WT-MtD) simulation is also generated along the folding pathway by considering radius of gyration (R gyr) as a collective variable (CV). It is very clear from the present WT-MtD study, that the initial bending starts at that hinge region, which may trigger other conformational changes. Both the protein-protein and protein-water HB time correlation functions are monitored along the folding pathway. The protein-protein (full or hinge region) HB time correlation functions are always found to be stronger than those of the protein-water time correlation functions. The dynamical balance between protein-protein and protein-water HB interactions favors the stabilization of the folded state.

Unbinding of fluorinated oxime drug from the AChE gorge in polarizable water: a well-tempered metadynamics study.

Despite the fact that fluorination makes a drug more lipophilic, the molecular level understanding of protein-fluorinated drug interactions is very poor. Due to their enhanced ability to penetrate the blood brain barrier, they are suitable for reactivation of organophosphorus inactivated acetylcholinesterase (AChE) in the central nervous system. We systematically studied the unbinding of fluorinated obidoxime (FOBI) and non-fluorinated obidoxime (OBI) from the active site gorge of the serine hydrolase AChE in mean field polarizable water by employing all atom molecular dynamics simulations. It is observed that the unbinding process is strongly influenced by cation-π, hydrogen bond (HB) and water bridge interactions. The FOBI drug interacts more strongly with the protein residues than OBI and this is also verified from quantum mechanical calculations. Distinct unbinding pathways for FOBI and OBI are observed as evident from the 1D and 2D potential of mean force of the unbinding profiles. The present study suggests that the FOBI drug is held more firmly in the gorge of AChE in comparison to OBI and may lead to higher reactivation efficiency of the inactivated enzyme.

An ab Initio Study on the Structure, Energetics, and Spectra of Cl-···(CO2)n Clusters.

Structures, energetics, and photoelectron spectral properties of Cl-···(CO2)n (n = 1-8) clusters are studied by ab initio electronic structure methods, namely, Møller-Plesset second-order perturbation theory (MP2) correlated consistent, aug-cc-pvtz basis functions. The most stable structure for each size is evaluated by using both bottom-up and top-down approaches. It is observed that CO2 molecules approach to the chloride anion in an asymmetric way except for Cl-···(CO2)8 cluster. We do observe the applicability of the simple classical electrostatic model for charge-quadrupole interactions to the solvation of the chloride anion by the solvent CO2. Both vertical electron detachment energies and solvation energies are calculated for all the clusters at the MP2 level. We do observe an excellent agreement between theory and experiment for the vertical detachment energy, solvation energy, and gas phase detachment energy of chloride anion. It is also observed that the detachment energy of the chloride anion is increased by 4.09 eV due to the solvation effect of bulk CO2 and it is quite small in contrast to the increase of 5.29 eV due to the solvation effect of polar solvent, water.

Ortho-7 bound to the active-site gorge of free and OP-conjugated acetylcholinesterase: cation-π interactions.

Despite the immense importance of cation-π interactions prevailing in bispyridinium drug acetylcholinesterase (AChE) complexes, a precise description of cation-π interactions at molecular level has remained elusive. Here, we consider a bispyridinium drug, namely, ortho-7 in three different structures of AChE, with and without complexation with organophosphorus (OP) compounds for detailed investigation using all atom molecular dynamics simulation. By quantum mechanical calculations, Y72, W86, Y124, W286, Y337, and Y341 aromatic residues of the enzyme are investigated for possible cation-π interactions with ortho-7. The cation-π interactions in each of the protein-drug complexes are studied using distance, angle, a suitable functional form of them, and electrostatic criteria. The variation of cation-π functional is remarkably consistent with that of the Columbic variation. It is clearly observed that cation-π interactions for some of the residues in the catalytic active site (CAS) and peripheral anionic site (PAS) of the enzyme are either enhanced or reduced based on the nature of OP conjugation (i.e., nerve gas, tabun or pesticide, fenamiphos) when compared with the OP-free enzyme. The strength of cation-π interaction is strongly dependent on the type OP conjugation. The effect of conjugation at CAS is also seen to influence the cation-π interaction at the PAS region. The variation of cation-π interactions on the type of conjugating OP compounds might be suggestive of a reason as to why wide spectrum drug against any OP poisoning is yet to arrive in the market.

A theoretical study on structures, energetics, and spectra of Br-.nCO2 clusters: towards bridging the gap between micro-domain and macro-domain.

Structures, energetics, and spectra of Br(-).nCO(2) (n = 1-8) clusters are studied based on ab initio electronic structure theory. The geometry of each size of clusters is evaluated by employing second-order Moller-Plesset (MP2) perturbation theory. It is observed that the solvent CO(2) molecules approach the bromide moiety from one side in an asymmetric fashion except for the Br(-).8CO(2) cluster. Simple electrostatic model for charge-quadrupole interactions is valid for the Br(-).nCO(2) clusters. Reduced variational space based energy decomposition method shows that the electrostatic interaction is the major component and polarization and charge transfer energies are the other significant components of the total interaction energy. Both adiabatic and vertical electron detachment energies and solvation energies are calculated at MP2 level of theory. We have observed an excellent agreement between theory and experiment for the vertical detachment and solvation energies. Calculated quantities based on the analytical expression which connects the finite domain to macroscopic one are found to be very good in agreement with the available experimental results. The present study reveals a 2.6 eV increase in the detachment energy of bromide anion due to the solvation effect of CO(2), which is relatively small compared to that of the corresponding 4.7 eV increase in detachment energy in water.

Conformationally averaged vertical detachment energy of finite size NO3(-)·nH2O clusters: a route connecting few to many.

We report conformationally averaged VDEs (VDE(w)(n)) for different sizes of NO(3)(-)·nH(2)O clusters calculated by using uncorrelated HF, correlated hybrid density functional (B3LYP, BHHLYP) and correlated ab intio (MP2 and CCSD(T)) theory. It is observed that the VDE(w)(n) at the B3LYP/6-311++G(d,p), B3LYP/Aug-cc-Pvtz and CCSD(T)/6-311++G(d,p) levels is very close to the experimentally measured VDE. It is shown that the use of calculated results of the conformationally averaged VDE for small-sized solvated negatively-charged clusters and a microscopic theory-based general expression for the same provides a route to obtain the VDE for a wide range of cluster sizes, including bulk.

Global minimum-energy structure and spectroscopic properties of I2(*-) x n H2O clusters: a Monte Carlo simulated annealing study.

The vibrational (IR and Raman) and photoelectron spectral properties of hydrated iodine-dimer radical-anion clusters, I(2)(*-) x n H(2)O (n=1-10), are presented. Several initial guess structures are considered for each size of cluster to locate the global minimum-energy structure by applying a Monte Carlo simulated annealing procedure including spin-orbit interaction. In the Raman spectrum, hydration reduces the intensity of the I-I stretching band but enhances the intensity of the O-H stretching band of water. Raman spectra of more highly hydrated clusters appear to be simpler than the corresponding IR spectra. Vibrational bands due to simultaneous stretching vibrations of O-H bonds in a cyclic water network are observed for I(2)(*-) x n H(2)O clusters with n > or = 3. The vertical detachment energy (VDE) profile shows stepwise saturation that indicates closing of the geometrical shell in the hydrated clusters on addition of every four water molecules. The calculated VDE of finite-size small hydrated clusters is extrapolated to evaluate the bulk VDE value of I(2)(*-) in aqueous solution as 7.6 eV at the CCSD(T) level of theory. Structure and spectroscopic properties of these hydrated clusters are compared with those of hydrated clusters of Cl(2)(*-) and Br(2)(*-).