pKa calculations in solution and proteins with QM/MM free energy perturbation simulations: a quantitative test of QM/MM protocols

The accuracy of biological simulations depends, in large part, on the treatment of electrostatics. Due to the availability of accurate experimental values, calculation of pKa provides stringent evaluation of computational methods. The generalized solvent boundary potential (GSBP) and Ewald summation electrostatic treatments were recently implemented for combined quantum mechanical and molecular mechanics (QM/MM) simulations by our group. These approaches were tested by calculating pKa shifts due to differences in electronic structure and electrostatic environment; the shifts were determined for a series of small molecules in solution, using various electrostatic treatments, and two residues (His 31, Lys 102) in the M102K T4-lysozyme mutant with large pKa shifts, using the GSBP approach. The calculations utilized a free energy perturbation scheme with the QM/MM potential function involving the self-consistent charge density functional tight binding (SCC-DFTB) and CHARMM as the QM and MM methods, respectively. The study of small molecules demonstrated that inconsistent electrostatic models produced results that were difficult to correct in a robust manner; by contrast, extended electrostatics, GSBP, and Ewald simulations produced consistent results once a bulk solvation contribution was carefully chosen. In addition to the electrostatic treatment, the pKa shifts were also sensitive to the level of the QM method and the scheme of treating QM/MM Coulombic interactions; however, simple perturbative corrections based on SCC-DFTB/CHARMM trajectories and higher level single point energy calculations were found to give satisfactory results. Combining all factors gave a root-mean-square difference of 0.7 pKa units for the relative pKa values of the small molecules compared to experiment. For the residues in the lysozyme, an accurate pKa shift was obtained for His 31 with multiple nanosecond simulations. For Lys 102, however, the pKa shift was estimated to be too large, even after more than 10 nanosecond simulations for each lambda window; the difficulty was due to the significant, but slow, reorganization of the protein and water structure when Lys 102 was protonated. The simulations support that Lys 102 is deprotonated in the X-ray structure and the protein is highly destabilized when this residue is protonated.     

Analysis of Equilibrium and Kinetics of Chromium-Fluoride Complexation from Spectroscopic Data via Chemometrics Methods

IntroductionStudies on reversible kinetic systems are consi-dered as a hotspot of chemical and biochemical kineticresearches[1,2]. Of late, some researches have been fo-cused on the simultaneous optimization of the obverseand reverse rate constants[3,4].H…     

Carbonyldinitrosyltris(fluorosulfato)tungstate(II) and ‐Molybdate(II) Anions: Synthesis,Spectroscopy, and Density Functional Theory Calculations

Carbonyldinitrosyltris(fluorosulfato)tungstate(II) and ‐molybdate‐(II) anions, [fac‐M(CO)(NO)₂(SO₃F)₃]^? (M=W, Mo), which are novel weakly coordinating anions that contain a metal carbonyl/nitrosyl moiety, have been generated in fluorosulfonic acid and completely characterized by multinuclear NMR, IR, and Raman spectroscopy as well as ESI mass spectrometry. ESI MS measurements performed for the first time on a superacidic solution system unambiguously reveal the formation of the monoanionic, mononuclear W and Mo complexes formulated as [M(CO)(NO)₂(SO₃F)₃]^? (M=W, Mo). Multinuclear NMR spectroscopic studies at natural abundance and ¹³C and ¹⁵N enrichment clearly indicate the presence of one CO ligand, two equivalent NO ligands, and two types of nonequivalent SO₃F^? groups in a 2:1 ratio. The IR and Raman spectra reveal that the two equivalent NO ligands have a cis conformation, thus indicating a fac structure. Density functional calculations at the B3LYP level of theory predict that these anions have a singlet ground state (¹A′) with a C_s symmetry along with C–O and N–O vibrational frequencies that are in agreement with the experimental observations. Mulliken population analysis shows that the monovalent negative charge is dispersed on the bulky sphere, the surface of which is covered by all the negatively charged O and F atoms with charge densities much lower than SO₃F^?, suggesting that [fac‐M(CO)(NO)₂(SO₃F)₃]^? (M=W, Mo) are weakly nucleophilic and poorly coordinating anions.     

Rheological Behavior for Mica-filled Polypropylene Composite Melts

The study on rheological properties of a series of mica-filled polypropylene (PP) composites was carried out. The influence of surface-treatment of mica particles on dynamic rheological behavior of the composites were dealt with. The viscosity (η) and dynamic modulus ( G‘ ) of the composite melts were higher than those of PP matrix, especially those for systems treated with silane, which was attributed to the interfacial adhesion enhancement. However, surface-treatment of mica by titanate resulted in lower η and G‘, as compared with the treatment by silane. The reason for this is believed to be the formation of the mono-molecular layer on the mica surface.     

A small molecule with osteogenesis-inducing activity in multipotent mesenchymal progenitor cells

Purmorphamine, which is a 2,6,9-trisubstituted purine compound, was discovered through cell-based high-throughput screening from a heterocycle combinatorial library. It differentiates multipotent mesenchymal progenitor cells into an osteoblast lineage. It will serve as a unique chemical tool to study the molecular mechanisms of osteogenesis of stem cells and bone development.     

化学镀钴基合金镀液中钴的快速测定

研究了采用显色剂 苦胺酸偶氮变色酸对化学镀钴基合金镀液中钴含量进行测定的试验条件,在pH11的氨 氯化铵缓冲溶液中,钴与显色剂配合物的最大吸收峰在650nm波长处,钴(Ⅱ)在0～60μg/25ml范围内服从比耳定律,表观摩尔吸光系数为3.1×104L·mol-1·cm-1。该法测定钴的选择性好,在大量镍存在下,也能准确测定,对镀液样品进行了测定,相对标准偏差小于1%,结果满意。     

Synthesis, Structure and Conductivity of the New Charge-transfer Salt (ET)_2(CH_2=CH-CH_2-SO_3)·H_2O

ET is one of the most famous electron-donor molecules, which forms charge-transfer complexes (abbr. CT-complexes) with various types of counterions. These complexes have received intense attention because a wide range of physical properties such as conductivity and superconductivity1, ferromagnetism2-4 and nonlinear optical properties5 was found in these materials. Although the majority of the ET-based CT-complexes were prepared by combining with inorganic counterions, CT-complexes with o…     

Quantum mechanics/molecular mechanics studies of triosephosphate isomerase-catalyzed reactions: effect of geometry and tunneling on proton-transfer rate constants

The role of tunneling for two proton-transfer steps in the reactions catalyzed by triosephosphate isomerase (TIM) has been studied. One step is the rate-limiting proton transfer from Calpha in the substrate to Glu 165, and the other is an intrasubstrate proton transfer proposed for the isomerization of the enediolate intermediate. The latter, which is not important in the wild-type enzyme but is a useful model system because of its simplicity, has also been examined in the gas phase and in solution. Variational transition-state theory with semiclassical ground-state tunneling was used for the calculation with potential energy surface determined by an AM1 method specifically parametrized for the TIM system. The effect of tunneling on the reaction rate was found to be less than a factor of 10 at room temperature; the tunneling becomes more important at lower temperature, as expected. The imaginary frequency (barrier) mode and modes that have large contributions to the reaction path curvature are localized on the atoms in the active site, within 4 A of the substrate. This suggests that only a small number of atoms that are close to the substrate and their motions (e.g., donor-acceptor vibration) directly determine the magnitude of tunneling. Atoms that are farther away influence the effect of tunneling indirectly by modulating the energetics of the proton transfer. For the intramolecular proton transfer, tunneling was found to be most important in the gas phase, to be similar in the enzyme, and to be the smallest in water. The major reason for this trend is that the barrier frequency is substantially lower in solution than in the gas phase and enzyme; the broader solution barrier is caused by the strong electrostatic interaction between the highly charged solute and the polar solvent molecules. Analysis of isotope effects showed that the conventional Arrenhius parameters are more useful as experimental criteria for determining the magnitude of tunneling than the widely used Swain-Schaad exponent (SSE). For the primary SSE, although values larger than the transition-state theory limit (3.3) occur when tunneling is included, there is no clear relationship between the calculated magnitudes of tunneling and the SSE. Also, the temperature dependence of the primary SSE is rather complex; the value of SSE tends to decrease as the temperature is lowered (i.e., when tunneling becomes more significant). For the secondary SSE, the results suggest that it is more relevant for evaluating the "coupled motion" between the secondary hydrogen and the reaction coordinate than the magnitude of tunneling. Although tunneling makes a significant contribution to the rate of proton transfer, it appears not to be a major aspect of the catalysis by TIM at room temperature; i.e., the tunneling factor of 10 is "small" relative to the overall rate acceleration by 10(9). For the intramolecular proton transfer, the tunneling in the enzyme is larger by a factor of 5 than in solution.     

铅烟除尘特性研究

简述静电除尘的电晕放电、尘粒荷电、尘粒运动与捕集的基本原理;重点讨论了铅烟高压静电发生器的绝缘结构、电场特性、低压回路、高压回路、本体设计等.通过研究得出结论:铅烟除尘器本体可采用直径800 mm圆柱形宽极间距结构,其高压绝缘可采用3 240与3 260环氧玻璃布作为主绝缘体,高压采样系统宜采用高压电阻直接取样方式,响应快,控制灵活.     

板柱结构的应用研究

通过对国内外板柱结构研究成果的总结与分析,得出结论:国内外对板柱节点的静力性能研究较多,对其动力性能,尤其是板柱结构体系的动力性能研究较少;认为有必要对其进行动力性能的实验研究;并提出了钢筋混凝土板柱结构抗震设计建议方法。