On the Concept of Orbital Steering in Catalytic Reactions

1,050

700

It is pointed out that translational and (overall) rotational motions provide the important entropic driving force for enzymic and intramolecular rate accelerations and the chelate effect; internal rotations and unusually severe orientational requirements are generally of secondary importance. desolvation. Unequivocal evidence that theories giving rate accelerations on the order of 55 AM from entropic factors are wrong or incomplete is provided by several intramolecular reactions, such as ring closures of succinate derivatives, in which the presence of one or more free rotations ensures that a reacting group can move out of an unfavorable conformation so that the fraction of the starting material in a high-energy, strained or desolvated form will be negligible. The comparison between intra-and intermolecular reactions may be based on the free energy of either the transition state, from rate measurements, or the product, from equilibrium measurements, relative to the starting material; the latter comparison has the advantage that the structure of the product is known. Thus, the equilibrium constant for succinic anhydride formation (Eq. 1) is3 X 105(1) more favorable than that for acetic anhydride formation from the free acids, which implies an "effective concentration" of 3 X 105 M of the carboxylic acid groups of succinic acid relative to each other (2, 9), and the "effective concentration" of the neighboring carboxylate group that determines the rate of anhydride formation from substituted monophenyl succinate anions (Eq. 2) is about 105 M (4,10,11

Section: Rotationsmentioning

confidence: 89%

Section: Rotationsmentioning

confidence: 99%

Entropic Contributions to Rate Accelerations in Enzymic and Intramolecular Reactions and the Chelate Effect

Page

Jencks

1971

1,050

700

“…Such a mechanism requires that the approach of the reacting molecules is restricted to a very narrow angular range by a steep potential energy surface in the direction perpendicular to the reaction coordinate. This proposal can be excluded once the actual energetics is estimated (5,41). (iii) The low-barrier hydrogen bond mechanism (20,21).…”

mentioning

confidence: 99%

Computer simulations of enzyme catalysis: Finding out what has been optimized by evolution

Warshel

Florián

1998

121

108

The origin of the catalytic power of enzymes is discussed, paying attention to evolutionary constraints. It is pointed out that enzyme catalysis ref lects energy contributions that cannot be determined uniquely by current experimental approaches without augmenting the analysis by computer simulation studies. The use of energy considerations and computer simulations allows one to exclude many of the popular proposals for the way enzymes work. It appears that the standard approaches used by organic chemists to catalyze reactions in solutions are not used by enzymes. This point is illustrated by considering the desolvation hypothesis and showing that it cannot account for a large increase in k cat relative to the corresponding k cage for the reference reaction in a solvent cage. The problems associated with other frequently invoked mechanisms also are outlined. Furthermore, it is pointed out that mutation studies are inconsistent with ground state destabilization mechanisms. After considering factors that were not optimized by evolution, we review computer simulation studies that reproduced the overall catalytic effect of different enzymes. These studies pointed toward electrostatic effects as the most important catalytic contributions. The nature of this electrostatic stabilization mechanism is far from being obvious because the electrostatic interaction between the reacting system and the surrounding area is similar in enzymes and in solution. However, the difference is that enzymes have a preorganized dipolar environment that does not have to pay the reorganization energy for stabilizing the relevant transition states. Apparently, the catalytic power of enzymes is stored in their folding energy in the form of the preorganized polar environment.Enzymatic reactions are involved in the acceleration and control of most biological processes. Thus, the understanding of the origin of the enormous catalytic power of enzymes is one of the important goals in molecular biology. Unfortunately, despite the enormous progress in structural and biochemical studies of enzymes, we still cannot use direct experiments to determine uniquely what are the most important factors in enzyme catalysis. It is quite obvious that enzymes reduce the activation free energies of their reactions, but, as will be shown in this work, it does not follow that evolution can do ''everything'' and that all possible mechanisms (e.g., entropy, strain, dynamic effects, etc.) can provide effective ways of catalyzing enzymatic reactions. Finding out what free-energy factors can help in catalysis is far from trivial because no current experimental technique can provide direct correlation between the structure of an enzymesubstrate complex (ES) and the detailed contributions to its transition state energy. Such correlation can be established, at least in principle, by using computer simulation approaches.This work will address the general problem of enzyme catalysis and the importance of using energy-based considerations for resolving this problem. It...

“…* As discussed earlier, for real molecules larger than water, A and B refer to the reactive groups, e.g., an OH of glucose, a phosphorus of ATP, etc., which are essentially the size of water molecules. This calculation has been criticized by Bruice and coworkers on the grounds that (a) real molecules may have a net attraction or repulsion (9), (b) that kintra/kinter for many reactions is actually far greater than 55/n, and hence the proximity correction is incorrect (9, 12), and (c) that a kintrt/kinstr ratio of 108 leads to angles (1/GA) much smaller (0.1°) than reasonable values for bending vibrational amplitudes (9).In regard to (a), the purpose of the proximity derivation is to obtain the idealized entropic correction. The assumptions of ideality were clearly stated (11) and methods for correcting for deviations of real molecules from idealized behavior have been described qualitatively (11) and quantitatively (10).…”

mentioning

confidence: 99%

Theoretical Aspects of Orbital Steering

Dafforn

Koshland

1971

A calculation based on transition-state theory leads to the conclusion that rate accelerations of 10'-1O could be achieved in In a previous paper, the magnitudes of contributions from bending vibrations and the distribution of approach orientations were considered with the use of a modified collisiontheory approach (10). In this paper contributions of rotational entropy, bending, and stretching vibrations are considered from the standpoint of transition-state theory. PROXIMITY AND ORIENTATIONThe calculation of orientation factors relative to a bimolecular reaction depends on the relationship between orientation and proximity illustrated in Fig. 1. The assumptions made in the original derivation of the proximity correction (11) were: (a) that molecules (or reactive atoms) A and B are the size of water molecules, (b) that there is no net attraction or repulsion between A, B, and/or solvent, and (c) that a molecule with no orientational preferences can react with any of its n nearest neighbor molecules. A molecule, A, which has an orientational preference such that it can react at 1/0A of its solid surface, has a probability of n(B)/550A of being in a reactive relationship with molecule B, which has no orientational preference. The rate acceleration expected, therefore, in a perfectly oriented and juxtaposed AB pair (as on an enzyme surface), compared to a random collision process when (B) = 1 M, would be (55/n)OA. The rate acceleration for two molecules, both of which have orientational requirements, would be (55/n)OAOB.* As discussed earlier, for real molecules larger than water, A and B refer to the reactive groups, e.g., an OH of glucose, a phosphorus of ATP, etc., which are essentially the size of water molecules. This calculation has been criticized by Bruice and coworkers on the grounds that (a) real molecules may have a net attraction or repulsion (9), (b) that kintra/kinter for many reactions is actually far greater than 55/n, and hence the proximity correction is incorrect (9, 12), and (c) that a kintrt/kinstr ratio of 108 leads to angles (1/GA) much smaller (0.1°) than reasonable values for bending vibrational amplitudes (9).In regard to (a), the purpose of the proximity derivation is to obtain the idealized entropic correction. The assumptions of ideality were clearly stated (11) and methods for correcting for deviations of real molecules from idealized behavior have been described qualitatively (11) and quantitatively (10). This procedure of deriving the equation for ideal behavior and correcting for deviations in real molecules is standard practice in similar derivations such as ideal-gas laws, Debye-Huckel theory, perfect-solution theory, etc. In regard to objection (b), it is our assumption that an experimentally observed kintra/kinter ratio involves many factors including proximity, orientation, ring strain, etc. The proximity derivation was devised to understand the fraction of the observed ratio contributed by proximity; the fact that many observed kintra/kinter ratios are greater tha...