Solvent structure representation

Fig. 9. Structural representation of a 48-member DHPM library. Given are the reaction parameters in the format conditions/temperature (°)/reaction time (min)/yield (%). Conditions refers to the solvent/catalyst systems A-E specified in Fig. 8.

In its current formulation the ASEP/MD method introduces a dual representation of the solute molecule. At each cycle of the ASEP/MD calculation, the solute charge distribution is updated using quantum mechanics but during the molecular dynamics simulations the solute charge distribution is represented by a set of fixed point charges. The use of an inadequate set of charges in the solute description can introduce errors into the estimation of the solvent structure, and hence of the solute s properties... 

Sequences of the representative proteins are displayed in JOY protein sequence/ structure representation (http //www-cryst.bioc.cam.ac.uk/ joy/). The representations are uppercase for solvent inaccessible, lowercase for solvent accessible, red for a helix, blue for strand, maroon for 310 helix, bold for hydrogen bond to main chain amide, underline for hydrogen bond to main chain carbonyl, cedilla for disulfide bond, and italic for positive angle. The query sequence is displayed in all capital letters. The consensus secondary structure (a for a helix, b for strand, and 3 for 310 helix) as defined, if greater than 70% of the residues in a given position in that particular conformation, is given underneath. 

Reactions. Chemical reactions extend the structure representation by adding information about what role the structure plays in the reaction (reactant, catalyst, solvent, product, etc.). Reaction representation may also include information about what bonds are made or broken during the reaction, and which atoms are involved in reacting centers. It is also common to use a hierarchical organization for reaction information (reaction > variation > reactants, catalysts, solvents, products, etc.). 

D structural coordinates The protein is composed of a chain of amino acids, which in turn are composed of atoms. The position of these atoms can be inferred from experimental measurements, most prominently, X-ray diffraction patterns or NMR spectra. Therefore, a very detailed description of a protein is given by the exact (x, y, z) coordinates of all the protein s atoms. It has to be kept in mind, however, that structure coordinates are still an abstraction of the protein in its actual environment interacting with solvent and/or other macromolecules. This is due to experimental measurement errors, crystallization effects, and the static picture implicated by the coordinates. In addition, it is not necessarily true, that the most accurate or comprehensive information, say regarding protein function, can be inferred best from the most detailed structural representation. 

Fig. 4.1. General structure of the potential of mean force for an atomic recombination reaction. The second minimum occurs at a distance corresponding to a separation of the atoms by one solvent molecule. To illustrate the effects of solvent structure, the effective hard-sphere representations (cf. Section VI) of the solute and solvent atoms are also shown.

Fig. 2. Three-dimensional structural representations for zinc metall-oproteins. Comparison of the zinc ion-protein bonding interactions for zinc requiring enzymes (A—C) with the zinc-insulin hexamer (D, E). (A) Human carbonic anhydrase C, redrawn from Ref. (47) with permission. (B) Bovine carboxypeptidase Ay, redrawn from Ref. 30) with permission. (C) Bacillus thermoprotedyticus thermolysin, redrawn from Ref. 45) with permission. (D) and (E) Porcine Zn-insulin hexamer, taken from Ref. 48) with permission. The composite electron density maps in (D) and (E) show that each of the two zinc atoms present in the hexamer is within inner sphere bonding distance of three solvent molecules and three histidyl imidazolyl groups in an octahedral array about the metal ion. The position of one of the three equivalently positioned solvent molecules is indicated in (D). The electron density map in (E) shows the relative orientations of the three histidyl residues (His-BlO). (The atomic positions of one of the three equivalent histidyl groups are shown)...

Since the early transition state does not involve covalent interaction with the nucleophile, the rate-determining intermediate also does not involve covalent interaction with the nucleophile, and is best represented as an ion pair. A structural representation of this ion pair cannot be specified precisely, but certainly there has been massive electron reorganization with little covalent interaction between the nuclei in the bond being broken. Mutual polarization of the carbonium ion and counter-ion can be assumed, as well as coulombic attraction. The intermediate formed in the rate-determining step is then rapidly converted to an intermediate which does involve covalent interaction with solvent or other nucleophiles present. Thus, the rate-determining step is unimolecular, and the observed kinetics are first-order. As will be seen shortly, the stereochemical course of the reaction can also be accommodated. 

In many cases explicit solvent models are more useful than implicit models. Examples include simulations in which a detailed picture of solvent structure is one of the goals and cases for which there is evidence that a particular structural feature of the solvent is playing a key role (e.g., a specific water-macromolecule hydrogen bond), although explicit representation of some water molecules combined with implicit solvation may suffice. MD simulations used to study kinetic, or time-dependence, properties of macromolecular processes, comprise another important example. 

In contrast, there will be many cases where continuum solvent models are less useful. These include situations where one of the goals of the simulation is to obtain a detailed picture of solvent structure, or where there is evidence that a particular structural feature of the solvent is playing a key role (for example, a specific water-macromolecule hydrogen bond). In these situations, however, explicit representation of some water combined with implicit solvation may suffice. Another example is when molecular dynamics simulations are used to study kinetic, or time-dependent phenomena. The absence of the frictional effects of solvent will lead to overestimation of rates. In addition, more subtle time-dependent effects arising from the solvent will be missing from continuum models. Continuum solvent models are in effect frilly adiabatic, in the sense that for any instantaneous macromolecular conformation, the solvent is taken to be completely relaxed. For electrostatic effects, this implies instantaneous dielectric and ionic double layer relaxation rates, and for the hydrophobic effect, instantaneous structural rearrangement. An exception would be dielectric models that involve a frequency-dependent dielectric. Nevertheless, continuum solvent models should be used with caution in studying the time dependence of macromolecular processes. 

The 20 MHz proton-decoupled spectra of isotactic and syndiotactic PMMA at 38 C in pyridine-d5 (solvent peaks eliminated). Each spectrum represents 7000 accumulated FID s. Symbols m and r refer to meso and racemic stereochemical relationships between adjacent repeat units. Structural representation of syndiotactic and isotactic stereochemical triads are included above the respective spectrum the S3nnbol R represents the methyl ester side group. (Figure from reference 2.)... 

The representation of a chemical reaction should include the connection table of all participating species starting materials, reagents, solvents, catalysts, products) as well as Information on reaction conditions (temperature, concentration, time, etc.) and observations (yield, reaction rates, heat of reaction, etc.). However, reactions are only Insuffclently represented by the structure of their starting materials and products,... 

It is possible to go beyond the SASA/PB approximation and develop better approximations to current implicit solvent representations with sophisticated statistical mechanical models based on distribution functions or integral equations (see Section V.A). An alternative intermediate approach consists in including a small number of explicit solvent molecules near the solute while the influence of the remain bulk solvent molecules is taken into account implicitly (see Section V.B). On the other hand, in some cases it is necessary to use a treatment that is markedly simpler than SASA/PB to carry out extensive conformational searches. In such situations, it possible to use empirical models that describe the entire solvation free energy on the basis of the SASA (see Section V.C). An even simpler class of approximations consists in using infonnation-based potentials constructed to mimic and reproduce the statistical trends observed in macromolecular structures (see Section V.D). Although the microscopic basis of these approximations is not yet formally linked to a statistical mechanical formulation of implicit solvent, full SASA models and empirical information-based potentials may be very effective for particular problems. 

A more detailed representation of the reaction requires more intimate knowledge of the enolate structure. Studies of ketone enolates in solution indicate that both tetrameric and dimeric clusters can exist Tetrahydrofliran, a solvent in which many synthetic reactions are performed, favors tetrameric structures for the lithium enolate of isobutyr-ophenone, for example. ... 

It is important to note that most molecules are not rigid but may prefer a distrinct structure and the conformation of a molecule strongly depends on its specific environment. Hence, the crystal structure of a drug does not have to correspond to the receptor bound conformation. Also, a conformation in solution depends on the nature of the solvent and measuring conditions, and may change when the molecule is bound to the receptor [4]. In addition, different receptors or receptor subtypes can bind the same drug in different conformations. It is a general assumption and observation, but by far not a strict condition, that the conformation in aqueous solution is similar to the bound conformation and is a better representation of the bioactive conformation than an X-ray structure of the isolated molecule in the crystalline state. 

Mechanistic studies have been designed to determine if the concerted cyclic TS provides a good representation of the reaction. A systematic study of all the E- and Z-decene isomers with maleic anhydride showed that the stereochemistry of the reaction could be accounted for by a concerted cyclic mechanism.19 The reaction is only moderately sensitive to electronic effects or solvent polarity. The p value for reaction of diethyl oxomalonate with a series of 1-arylcyclopentenes is —1.2, which would indicate that there is little charge development in the TS.20 The reaction shows a primary kinetic isotope effect indicative of C—H bond breaking in the rate-determining step.21 There is good agreement between measured isotope effects and those calculated on the basis of TS structure.22 These observations are consistent with a concerted process. 

It has been demonstrated that ionic intermediates are not involved in the epoxidation reaction. The reaction rate is not very sensitive to solvent polarity.71 Stereospecific syn addition is consistently observed. The oxidation is therefore believed to be a concerted process. A representation of the transition structure is shown below. 

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