Enzyme potential surfaces

Protein dipoles-Langevin dipoles model (PDLD), 123-125,124 Protein potential surfaces, see Enzyme potential surfaces... 

This ground state provides an analytical potential surface for the reacting system in the enzyme-active site. 

FIGURE 9.1. The potential surface for proton transfer reaction and the effect of constrainir the tiA B distance. The figure demonstrates that the barrier for proton transfer increasi drastically if the A — B distance is kept at a distance larger than 3.5 A. However, in solutic and good enzymes the transfer occurs through pathway a where the A - B distance is arour 2.7 A. 

The entropic hypothesis seems at first sight to gain strong support from experiments with model compounds of the type listed in Table 9.1. These compounds show a huge rate acceleration when the number of degrees of freedom (i.e., rotation around different bonds) is restricted. Such model compounds have been used repeatedly in attempts to estimate entropic effects in enzyme catalysis. Unfortunately, the information from the available model compounds is not directly transferable to the relevant enzymatic reaction since the observed changes in rate constant reflect interrelated factors (e.g., strain and entropy), which cannot be separated in a unique way by simple experiments. Apparently, model compounds do provide very useful means for verification and calibration of reaction-potential surfaces... 

Barium, effectiveness as cofactor for, see also Enzyme cofactors phospholipase, 204 SNase, 200-204 Bond-breaking processes, 12 potential surfaces for, 13-14, 18-20 in solutions, 22,46-54... 

See also Enzyme cofactors downhill trajectories for, 196,197 mechanism of catalytic reaction, 190-192 metal substitution, 200-204 potential surfaces for, 192-195,197 rate-limiting step of, 190 reference solution reaction for, 192-195,... 

Transition state theory, 46,208 Transmission factor, 42,44-46,45 Triosephosphate isomerase, 210 Trypsin, 170. See also Trypsin enzyme family active site of, 181 activity of, steric effects on, 210 potential surfaces for, 180 Ser 195-His 57 proton transfer in, 146, 147 specificity of, 171 transition state of, 226 Trypsin enzyme family, catalysis of amide hydrolysis, 170-171. See also Chymotrypsin Elastase Thrombin Trypsin Plasmin Tryptophan, structure of, 110... 

The applications of NN to solvent extraction, reported in section 16.4.6.2., suffer from an essential limitation in that they do not apply to processes of quantum nature therefore they are not able to describe metal complexes in extraction systems on the microscopic level. In fact, the networks can describe only the pure state of simplest quantum systems, without superposition of states. Neural networks that indirectly take into account quantum effects have already been applied to chemical problems. For example, the combination of quantum mechanical molecular electrostatic potential surfaces with neural networks makes it possible to predict the bonding energy for bioactive molecules with enzyme targets. Computational NN were employed to identify the quantum mechanical features of the... 

N-Ribohydrolases have been found to be involved in novel pathways of purine salvage in protozoan parasites as well as in nucleic acid repair, and exhibit other interesting biological activities [178]. In order to investigate the molecular electrostatic potential surface of the enzyme from the trypanosome Crithidia fasci-culata, several l,4-dideoxy-l,4-imino-D-ribitol derivatives were synthesized as nucleoside analogues and their inhibitory powers were tested [179,180]. In the course of this work, l,4-dideoxy-l,4-imino-l(S)-phenyl-D-ribitol (97) was found to inhibit this enzyme with K 30 nmol/1. 

Figure 4 Electronic potential of the active site of (A) CYP2D1, (B) CYP2D2, (C) CYP2D3, (D) CYP2D4, and (E) CYP2D6. Grey, black, and white indicate negative, positive, and neutral electrostatic potentials, respectively. The electrostatic potential surfaces are shown in the same orientation as the enzyme shown in (F), with the heme group at the bottom of the active site. Source Modified from Ref. 11.

E-fS ES ES. The standard deviation of the distribution, (Atopen ) = 8.3 2ms, reflects the distribution bandwidth. For the individual T4 lysozyme molecules examined under the same enz unatic reaction conditions, we found that the first and second moments of the single-molecule topen distributions are homogeneous, within the error bars. The hinge-bending motion allows sufficient structural flexibility for the enzyme to optimize its domain conformation the donor fluorescence essentially reaches the same intensity in each turnover, reflecting the domain conformation reoccurrence. The distribution with a defined first moment and second moment shows typical oscillatory conformational motions. The nonequilibrium conformational motions in forming the active enzymatic reaction intermediate states intrinsically define a recurrence of the essentially similar potential surface for the enzymatic reaction to occur, which represents a memory effect in the enzymatic reaction conformational dynamics [12,41,42]. 

In order to gain a quantitative understanding of the catalytic power of enzymes, it is essential to be able to calculate the free-energy profiles for enzymatic reactions and the corresponding reference solution reactions. The common prescription of obtaining potential surfaces for chemical reactions involves the use of quantum mechanical (QM) computational approaches, and such approaches have become quite effective in treating small molecules in the gas phase (e.g., Ref. 5). However, here we are interested in chemical reactions in very large systems, which cannot be explored... 

As stated above, reliable studies of enzyme catalysis require accurate results for the difference between the activation barriers in enzyme and in solution. The early realization of this point led to a search for a method that could be calibrated using experimental and theoretical information of reactions in solution. It also becomes apparent that in studies of chemical reactions, it is more physical to calibrate surfaces that reflect bond properties (i.e., valence bond-based (VB-based) surfaces) than to calibrate surfaces that reflect atomic properties (e.g., molecular orbital-based surfaces). Furthermore, it appears to be very advantageous to force the potential surfaces to reproduce the experimental results of the broken fragments at infinite separation in solution. This can be easily accomplished with the VB picture. The resulting EVB method has been discussed extensively elsewhere,21 22 but its main features will be outlined below, because it provides the most direct microscopic connection to concepts of physical organic chemistry. 

Just to set the problem in a clear way for further considerations, we give in Fig. 5 the potential surface for the wild-type enzyme using pAias of 5.0 and 9.0 for (H20)a and Lys64 (taken from Ref. 50) and pKa — 0 for (H20), evaluated by the PDLD/S-LRA method as described in the previous section. 

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