Electrostatic potential substrate

The electrostatic potential is highly suitable for analyzing processes in which the initial step is the recognition by some system, such as an enzyme or receptor, that an approaching molecule, e.g. a substrate or drug, has certain key features that will promote (or hinder) their interaction, which is electrostatic in the early stages. For this purpose V(r) is computed in the outer regions of the molecule, perhaps in a plane but preferably on its surface, because this is what the enzyme, receptor, etc., sees or feels. There have been numerous such studies, some of which have been summarized in a variety of reviews [1, 2, 6, 7, 11, 69]. 

Figure 9.10 Up work function of alkali-promoted metals as a function of alkali coverage (see also Table 9.2). Down electrostatic potential around a single alkali atom adsorbed on jellium. The effective local work function at each position is the sum of the substrate work function and the value of the electrostatic potential in the figure (from Lang el at. [39]).

One approach, which has been used extensively in pharmacological areas [27], is to look for characteristic patterns of positive and negative regions that may enhance or inhibit a certain type of activity. The early stages of chug-receptor and enzyme-substrate interactions, in which the participants recognize each other through their outer electrostatic potentials, can be analyzed in this manner [28]. We were able, on this basis, to find qualitative trends in the toxicities of chlorinated dibenzo-p-dioxins and related systems [29]. 

Structure of water in the environment is not considered and (5) the contribudon to the total ionic strength, brought about by substrates or inhibitors when these are charged molecules, is assumed to be negligible. This treatment actually concerns only the influence of the electrostatic potential prevailing within the environment on the local concentration of protons and substrates. 

Most natural substrates of enzyme systems are charged molecules. Their local concentradon within any polyelectrolydc environment is given by Eq. (43). Therefore, as a second consequence of the presence of the electrostatic potential, the apparent Michaelis constant of the reac-... 

Figure 3/ for example/ places the lanosterol so as the 3f hydroxyl polar group lies over the propionate side chains. To reduce the complexity of this picture one can now replace the lanosterol structure by a surface canopy to represent the extent of the hydrophobic substrate binding site. There is also the facility to code this surface to signify the electronic properties of the substrates such as their electron density/ electrostatic potential/ or HOMO/LUMO values. Theoretical work of this type is currently suggesting quite remarkable complementarity of electron properties between bound substrates and protein binding sites. (10). 

Two of three nitrofluorobenzene isomers react with methoxide, but the third is unreactive. Obtain energies of methoxide anion (at left), ortho, meta and para-nitrofluorobenzene, and the corresponding ortho, meta and para-methoxide anion adducts (so-called Meisenheimer complexes). Calculate the energy of methoxide addition to each of the three substrates. Which substrate is probably unreactive What is the apparent directing effect of a nitro group Does a nitro group have the same effect on nucleophilic aromatic substitution that it has on electrophilic aromatic substitution (see Chapter 13, Problem 4) Examine the structures and electrostatic potential maps of the Meisenheimer complexes. Use resonance arguments to rationalize what you observe. 

Fig. 3.6 Solvent access surfaces (colors represent electrostatic potentials) showing the exposed tryptophan residue (as yellow van der Waals spheres) involved in oxidation of lignin and other high redox-potential substrates by VP (a) and LiP (b). Lignin can be directly oxidized by VP at the tryptophan radical, while LiP requires the simultaneous presence of VA (synthesized by the fungus) acting as an enzyme-bound mediator [74]. Based on VP and LiP crystal structures (PDB 2BOQ and 1LLP, respectively)...

The ability to both exist in a stable basal state and generate sufficiently oxidizing intermediates in order to specifically transform substrates is the challenge that heme peroxidases face. Redox potential (E°) play a critical role in determining a peroxidase ability to catalyze challenging oxidation reactions. However, it is not the only factor. As in other heme proteins, activity also depends on electrostatic interactions, substrate orientation, and active site topography [2],... 

A characteristic of immobilized enzymes that is often ignored is the potential partitioning of ions and substrates and/or products due to electrostatic potentials or hydrophobic moments. This factor could be used to advantage, for example, if the optimal conditions for enzyme activity do not match those of the process stream. To use the example cited earlier, a succinamidopropyl surface was shown by electrostatic partitioning of ions and independent chemical analysis to have 96 ymol charged groups/g dry beads (25). Attachment of 2 ymol trypsin/g did not significantly alter this characteristic. 

The descriptors developed to characterize the substrate chemotypes are obtained from a mixture of molecular orbital calculations and GRID probe-pharmacophore recognition. Molecular orbital calculations to compute the substrate s electron density distribution are the first to be performed. All atom charges are determined using the AMI Hamiltonian. Then the computed charges are used to derive a 3D pharmacophore based on the molecular electrostatic potential (MEP) around the substrate molecules. 

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