On the generation of catalytic antibodies by transition state analogues

The effective design of catalytic antibodies represents a major conceptual and practical challenge. It is implicitly assumed that a proper transition state analogue (TSA) can elicit a catalytic antibody (CA) that will catalyze the given reaction in a similar way to an enzyme that would evolve (or was evolved) to catalyze this reaction. However, in most cases it was found that the TSA used produced CAs with relatively low rate enhancement as compared to the corresponding enzymes, when these exist. The present work explores the origin of this problem, by developing two approaches that examine the similarity of the TSA and the corresponding transition state (TS). These analyses are used to assess the proficiency of the CA generated by the given TSA. Both approaches focus on electrostatic effects that have been found to play a major role in enzymatic reactions. The first method uses molecular interaction potentials to look for the similarity between the TSA and the TS and, in principle, to help in designing new haptens by using 3D quantitative structure-activity relationships. The second and more quantitative approach generates a grid of Langevin dipoles, which are polarized by the TSA, and then uses the grid to bind the TS. Comparison of the resulting binding energy with the binding energy of the TS to the grid that was polarized by the TS provides an estimate of the proficiency of the given CA. Our methods are used in examining the origin of the difference between the catalytic power of the 1F7 CA and chorismate mutase. It is demonstrated that the relatively small changes in charge and structure between the TS and TSA are sufficient to account for the difference in proficiency between the CA and the enzyme. Apparently the environment that was preorganized to stabilize the TSA charge distribution does not provide a sufficient stabilization to the TS. The general implications of our findings and the difficulties in designing a perfect TSA are discussed. Finally, the possible use of our approach in screening for an optimal TSA is pointed out.     

The transition state for metal-catalyzed dehalogenation

Substituent effects have been used to probe the nature of the transition state to catalytic carbon–halogen bond breaking. Kinetics measurements have determined the activation energies (E _act to C–Cl bond breaking on the Pd(111) surface and C–I bond breaking on the Pd(111) and Ag(111) surfaces. These barriers have been measured using alkyl halides with varying degrees of fluorine substitution. The activation energies have been correlated with the inductive or field substituent constants (σ_F) of the fluorinated alkyl groups in order to determine reaction constants (E _act=E₀+ρσ_F) for the dehalogenation reactions. In all three cases it has been found that the barriers are insensitive to inductive substituent effects and the reaction constants are all relatively small: ρ= −0.5± 1.0 kcal/mol for C–Cl cleavage on Pd(111), ρ= −0.3±0.8 kcal/mol for C–I cleavage on Pd(111), and ρ= −2.9±0.4 kcal/mol for C–I cleavage on Ag(111). This implies that the transition state for dehalogenation is homolytic and occurs early in the reaction coordinate. The implications of this result are discussed for catalytic dehalogenation processes such as hydrodechlorination. This revised version was published online in July 2006 with corrections to the Cover Date.     

Cassie状态到Wenzel状态转换的能量分析

从能量的角度分析了液滴在具有圆柱形阵列的硅片表面上从Cassie状态向Wenzel状态转换的条件。通过理论计算得到了液滴在不同参数的圆柱阵列上发生状态转换所需克服的能量势垒与液滴体积之间的关系曲线,并通过实验对体积大于2 μl的液滴做了验证。实验表明,对于体积大于2 μl的液滴可以通过增大液滴重力势能的方式实现从Cassie状态到Wenzel状态的转化,也可以保持液滴体积不变,通过增大圆柱阵列的柱间距的方法实现液滴从Cassie状态到Wenzel状态的转换。实验结果与理论分析保持一致。     

Glass transition and thermodynamic state of densified polymeric glasses

Differential scanning calorimetry (d.s.c.) and specific volume, V, measurements have been made on polystyrene glasses formed by cooling from the melt under pressure. Conventional glass temperatures, T_g(H) and T_g(V), defined by the points of intersection of enthalpy, H, or V curves for the glass and liquid agree well for one atmosphere glasses but show very different behaviour if the glass has been formed under pressure. This is due to the inability of the high pressure glasses to attain a suitable liquid conformation at atmospheric pressure. The thermodynamic state of densified glasses is discussed.     

The glassy state,ideal glass transition,and second‐order phase transition

According to Ehrenfest classification, the glass transition is a second‐order phase transition. Controversy, however, remains due to the discrepancy between experiment and the Ehrenfest relations and thereby their prediction of unity of the Prigogine‐Defay ratio in particular. In this article, we consider the case of ideal (equilibrium) glass and show that the glass transition may be described thermodynamically. At the transition, we obtain the following relations: and with Λ = (α_gβ_l − α_lβ_g)²/β_lβ_gΔα²; and The Prigogine‐Defay ratio is with Γ = TV(α_lβ_g − α_gβ_l)²/β_lβ_gΔβ, instead of unity as predicted by the Ehrenfest relations. Dependent on the relative value of ΔC_V and Γ, the ratio may take a number equal to, larger or smaller than unity. The incorrect assumption of perfect differentiability of entropy at the transition, leading to the second Ehrenfest relation, is rectified to resolve the long‐standing dilemma perplexing the nature of the glass transition. The relationships obtained in this work are in agreement with experimental findings. © 1999 John Wiley & Sons, Inc. J Appl Polym Sci 71: 143–150, 1999     

Ubiquitin folds through a highly polarized transition state

The small alpha/beta protein ubiquitin has been used as a model system for experimental and computational studies on protein folding for many years. Here, we present a comprehensive phi-value analysis and characterize the structure and energetics of the transition state ensemble (TSE). Twenty-seven non-disruptive mutations are made throughout the structure and a range of phi-values from zero to one are observed. The values cluster such that medium and high values and found only in the N-terminal region of the protein, whilst the C-terminal region has consistently low phi-values. In the TSE, the main alpha-helix appears to be fully formed (two phi-values which specifically probe helical structure are one) and the helix is stabilized by packing against the first beta-turn, which is partially structured. In striking comparison, the phi-values in the C-terminal region are all very low, suggesting that this region of the protein is largely unstructured in the TSE. Data are consistent with a nucleation-condensation mechanism in which there is a highly polarized folding nucleus comprising the first beta-hairpin and the alpha-helix. Data presented from the protein engineering study and phi-value analysis are compared with results from other experimental studies and also computational studies.     

Viscoelastic properties of linear polymers in the fluid state and their transition to the high-elastic state

The experimental results of the Viscoelastic properties of linear polymers of narrow molecular weight distribution (MWD) and of their mixtures have been analyzed and generalized. Based on the study of the properties of polymers of narrow MWD, we propose a classification of high molecular weight compounds. It specifies a distinct boundary between oligomers and polymers, assuming that the most important feature of polymers is the manifestation of large high-elastic recoverable deformations of entropy character. For polymers to be characterized, not the absolute molecular weight is essential, but the molecular weight referred to the boundary values. The corresponding state for polymers is attained at temperatures 100°C away from the glass temperature. The transition from the fluid to the high-elastic state with increasing deformation rate (or frequency for cyclic deformation) has been studied. Transition to the high-elastic state takes place over a narrow stress range (0.1-1.0 dynes/cm²), independent of molecular weight, whereas the critical deformation rates (frequencies), like viscosity, depend greatly on molecular weight. An increase in the amount of deformation shifts, to u certain extent, this transition to lower Kites of deformation (frequencies). In the region of deformation rates (frequencies) corresponding to the high-elastic state, the effect of large deformations during shear manifests itself largely in the tear-off of polymers Iron, the confining surfaces and in specimen rupture. Polydispersity has a strong effect on the properties of polymeric systems. As the rate of deformation is increased, the transition proceeds successively from the higher molecular weight components. This relaxational transition is tantamount to a change of the structure for polymeric systems. It is responsible for non-linear, particularly, non-Newtonian behavior of such systems. The transition to the high-elastic state and all the related phenomena are observed also in concentrated solutions of high molecular weight polymers. The long-term durability of un-cured rubbers in the high-elastic state is described by the same relationships.     

The glass transition and the glassy state in isotropic and liquid crystalline polymers

PVT-measurements on atactic polystyrene shows that the Ehrenfest equations, which describe a thermodynamic transformation of the second order, are not applicable for the glass transition. The introduction of one internal ordering parameter ζ in addition to the conventional variables T and P, is sufficient to describe the behaviour in case of atactic PS in the isotropic glassy state. The usually observed way dependences in the glassy state can be explained by the concept of ordering parameters. In recent years liquid crystalline side chain polymers were developed. The liquid crystalline phases of these polymers can be supercooled and frozen-in like isotropic liquids. As the nematic or smectic liquid crystalline structure freezes-in, and can be conserved by this process, glasses with anisotropic properties are obtained. These glasses show e.g. a high optical birefringence. The glass transition of the liquid crystalline polymers can only be described by the assumption of at least two parameters ζ_i. Therefore the Ehrenfest equations are not applicable for the glass transition of isotropic as well as anisotropic glasses.     

Structural-chemical modeling of transition of coals to the plastic state

The structural-chemical simulation of the formation of plastic state during the thermal treatment (pyrolysis, coking) of coals is based on allowance for intermolecular interactions in the organic matter. The feasibility of transition of coals to the plastic state is determined by the ratio between the onset plastic state (softening) and runaway degradation temperatures, values that depend on the petrographic composition and the degree of metamorphism of coals and the distribution of structural and chemical characteristics of organic matter.     

Rheology of a thermoplastic paste through the mushy state transition

The rheology of a highly filled thermoplastic paste employed in a novel continuous casting process was investigated across the melt-mushy zone temperature transition. The paste comprises of an ultrafine (or nano-particulate) zinc oxide powder (, 50 vol%) and a continuous phase consisting of a blend of organic waxes with an onset of solidification around . Data were collected over nine decades of shear rate, using controlled strain and controlled stress devices, steady shear and oscillatory modes, rotational rheometry, and capillary rheometry using the multi-pass technique. The melt rheology could be described using a Carreau-type constitutive model, with strong evidence of a low shear rate viscosity plateau and a possible high shear rate viscosity plateau, with a transition between the two described by a highly shear-thinning power-law region. Nearer the solidification temperature the material exhibited strong pseudo-plastic behaviour, and capillary flow appears to be determined by pressure-dependent slip behaviour.     

Enzymatic esterification and transesterification of N-protected Glu or Asp and synthesis of sweetener aspartam analogues by a new glutamic acid specific endopeptidase

Esterification and transesterification reactions are carried out in water miscible organic solvents by using a new glutamic acid specific endopeptidase, isolated from Bacillus lichenifonnis. Sweetener aspartam analogues syntheses are also described.     

Application of transition state theory to the study of materials containing acryloxy and acrylate units

We study the diffusion behavior of a probe, in monomers containing acryloxy and acrylate units that are commonly used in restorative dentistry. We apply a version of transition state theory with satisfactory results. Results show that transition state theory describes part of the underlying physics successfully thus reinforcing its applicability as a complement and extension to molecular dynamics simulations.     

Kinetic identification of a hydrogen bonding pair in the glucoamylase-maltose transition state complex

Molecular recognition and site-directed mutagenesis are usedin combination to identify kinetically, transition state interactionsbetween glucoamylase (GA) and the substrate maltose. Earlierstudies of mutant Glu180 – Gin GA had indicated a rolein substrate binding for Glul80 (Slerks, M.R., Ford, C., Reilly,P.J. and Svensson, B. (1990) Protein Engng, 3, 193–198).Here, changes in activation energies calculated from measuredk_cat/K_m values for a series of deoxygenated maltose analoguesindicate hydrogen bonding between the mutant enzyme and the3-OH group of the reducing end sugar ring. Using the same substrateanalogues and determining activation energies with wild-typeGA an additional hydrogen bond with the 2-OH group of maltoseis attributed to an interaction with the carboxylate Glu180.This novel combination of molecular recognition and site-directedmutagenesis enables an enzyme substrate transition state contactto be identified and characterized even without access to thethree dimensional structure of the enzyme. Given the distantstructural relationships between glucoamylases and several starchhydrolases (Svensson, B. (1988) FEBS Lett., 230, 72–76),such identified contacts may ultimately guide tailoring of theactivity of these related enzymes.     

The transition from the fixed to the fluidised state of binary-solid liquid beds

A peculiar phenomenon is observed when a binary-solid bed, in which the particle species possessing the larger minimum fluidization velocity is placed initially on top of the other, is brought from the fixed to the fluidised state. Contrary to the well known behaviour of mono-component beds, a single minimum fluidization velocity is not observed in this case and, more importantly, the fluid pressure drop can turn out to be considerably greater than the total effective weight of the particles. Particle–wall interactions are shown to be responsible for this latter effect. The problem is approached by considering differential horizontal slices of the bed with the simplification suggested by Janssen in 1895 that the ratio of vertical to horizontal solid pressure in a slice is constant—the Janssen constant K. Predictions of the model, which contains no adjustable parameters, are shown to be in excellent agreement with experimental measurements.     

Forced transition of cellulose macromolecules into the uncoiled state in amine oxide solutions

Conclusions -- The behavior of polymeric chains in dilute cellulose solutions in triethylamine oxide or in mixtures of this solvent with dimethylformamide under intense lengthwise flow, where the product of the velocity gradient by the chain relaxation time is approximately equal to unity, has been studied. It has been shown that under these conditions, the macromolecules go over into a practically completely uncoiled state.-- A decrease in the viscosity of the solvent as a result of increasing the experimental temperature, or selective solvation of the cellulose by molecules of TEAO, which takes place as a result of using a ternary mixture, shifts the region of the transition in the direction of larger velocity gradients.Translated from Khimicheskie Volokna, No. 2, pp. 22–24, March–April, 1993.     

Computer-assisted synthetic planning considering reaction kinetics based on transition state automated generation method

Organic synthesis facilitates the conversion of raw materials into high-value chemicals. Computer-assisted synthetic planning plays a vital role in designing synthetic pathways, which are usually evaluated by the reaction probability using deep learning models. However, this criterion is generally hard to describe real reaction behaviors such as reaction kinetics. Therefore, this article aims to establish a reaction kinetics-based retrosynthesis planning framework to design synthetic pathways with well-performed reaction kinetics. The key contribution of this work is developing a method for the GENeration of initial guesses of Transition States based on Reactive Sites (GENiniTS-RS) to automatically and fast generate the initial guesses of transition states for the transition state theory-based reaction kinetic model without sampling the minimum energy path from reactants to products. Finally, two case studies involving the design of synthetic pathways for aspirin and ibuprofen are presented to demonstrate the feasibility and effectiveness of the proposed framework.     

Solid state polyamidation of nylon salts: possible mechanism for the transition solid-melt

Solid state polyamidation of nylon salts may be accompanied, depending on the reaction conditions, by a typical transition of the process from the solid to the melt state. For an explanation of this phenomenon, dodecamethylenediammonium adipate, a typical salt with such a transitional behaviour, has been chosen for further study. The possibility of the formation of an eutectic system monomer-polymer has been excluded and the role of the water of polycondensation has been taken into account. Water quantitative determinations proved that a significant amount of the water produced, during the course of the reaction, cannot be removed out of the reacting grains. Due to the deliquescent behaviour of the monomer, it is proposed that this water accumulation results in the formation of lower melting point areas. Overlapping of the latter explains the transition observed.     

Change of the amorphous state by heat treatment below the glass transition temperature

This study was undertaken to elucidate the state of a polymer in the amorphous state through a change of motion of the molecular chain caused by heat treatment below the glass transition temperature. From dielectric measurements of amorphous poly(ethylene terephthalate) heat-treated below T_g, it was found that the average relaxation time, the distribution of relaxation time and the dielectric strength increase with increase of heat treatment. From these results, it was concluded that the amorphous state becomes more random by heat treatment.