Substrate binding has additional effects that enhance reaction rates, among which proximity and orientation gives the most obvious increase. There are two characteristics of enzyme-substrate binding, where the first one is that the binding brings together substrates and the reactive groups on the active site of the enzyme. The second one is that active site in the enzyme is extremely specific in the substrates, therefore making the reaction as efficient as possible. Proximity and orientation in enzyme-substrate interactions could align the reactive chemical groups and make them come together in an optimal orientation with the proper spatial relationship for a reaction to occur. Once the substrates are fixed this way, the enzymatic reaction behaves kinetically like an intramolecular process. It has been suggested that molecules are maximally reactive when their orbitals are aligned so the electronic energy of the transition state is minimized. The fewer nonproductive ways two groups are oriented, the faster they will react.

Rate Increase due to Proximity & Orientation Effect

Proximity effects describe the orientation and movement of the substrate molecules when binding to enzyme active sites, and are most readily observed by comparing equivalent inter- and intramolecular reactions. This effect of proximity and orientation is analogous to an effective increase in concentration of the reagents and endows the reaction an intramolecular character with a massive rate increase. Intramolecular reactions between groups that are tied together in a single molecule are faster than the corresponding intermolecular reactions between two independent molecules. Difference in rates are 3-4 orders of magnitude (intramolecular> intermolecular). This is mostly owing to the differences between the entropy changes that accompany inter- and intramolecular reactions. The entropy of the reactants is reduced in intramolecular reaction, which principally occurs during its preparation process and makes addition or transfer reactions less unfavorable, since the integration of two reactants into a single product could decrease the reduction in the overall entropy. The entropy decrease involved in the formation of the transition state has been moved to an earlier step, the binding of the substrates to form the enzyme-substrate complex. However, in the intermolecular reaction the formation of product involves a much larger loss of translational and rotational entropy.

Figure 1. Proximity effects and orientation effects on reaction rates.

Requirements for Catalysis

It has been stated that a close proximity between a substrate and an enzyme active site does not mean that a catalysis reaction will occur. The enzyme must guide or steer the substrate into the active site in a specific orientation to make the reaction actually occur, which is called orientation. With time elapsing, orientation has evolved and become more efficient and more significant though difficult to quantify. Other requirements for such a reaction to occur are changes in solvation and electronic overlap, as well as overcoming of Van der Waals forces. Orientation effects and induction of strain are needed to meet these requirements.

Figure 2. Proximity & orientation effects on HIV protease.

Reference

1. Page M I, Jencks W P. Entropic contributions to rate accelerations in enzymic and intramolecular reactions and the chelate effect. Proc Nat Acad Sci, 1971, 68 (8): 1678-1683.

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