Lock-and-key analogy

The basic problem with the lock and key analogy is that locks and keys are generally rigid structures while proteins and their substrates have substantial freedom of movement that is, proteins and their substrates have a number of conformations available to them in space and they change conformation a few billion times per second. So, our biological locks and keys are wobbly. 

The structural determinations also yielded a surprise. The shape of the enzyme changes when a purine is bound. The famous lock-and-key analogy [20] has a fallacy the shape of the lock is not static, but flexible. Awareness of these conformational changes critically aided our modeling efforts, allowing prediction of which parts of PNP could change shape to interact with a proposed inhibitor. 

The idea of complementarity in enzyme - substrate interactions was introduced by E. Fischer with his famous lock and key analogy.7 In modem terminology this would represent enzyme-substrate complementarity. The currently favored concept of enzyme-transition state complementarity was introduced by Haldane1 and elaborated by L. Pauling.2... 

The reason that the minor reactive intermediate leads to the major product is due to the large rate constant for hydrogenation (k ) associated with the S cycle compared to the R cycle. Clearly, the conventional lock and key analogy for the origin of enantioselectivity does not apply for this case since the selectivity is determined by kinetics of hydrogenation instead of thermodynamics of olefin binding. 

Since the proposition of the lock-and-key analogy by Emil Fischer (1894) several attempts have been done to understand the basis of enzymatic action. The key factor of rate acceleration by enzymes with a factor of 10IW or more (Kraut, 1977) has been thought to be the fit of transition state to the enzyme active site (Haldane, 1930 Pauling, 1946), however, it is still somewhat unclear what do we mean by the term fit. What are the real factors leading to the stabilisation of the transition state ... 

In the past, it was thought that a substrate fitted its active site in a similar way to a key fitting a lock. Both the enzyme and the substrate were seen as rigid structures with the substrate (the key) fitting perfectly into the active site (the lock) (Fig. 4.17). However, such a scenario does not explain how some enzymes can catalyse a reaction on a range of different substrates. It implies instead that an enzyme has an optimum substrate which fits it perfectly and which can be catalysed very efficiently, whereas all other substrates are catalysed less efficiently. Since this is not the case, the lock and key analogy is invalid. 

In this theory, it is assumed that there is a rigid receptor site and that morphine and its analogues fit into the site in a classic lock-and-key analogy. 

The notion of specific dmg action is most often described by a lock-and- key analogy. The drug is seen as the key that acts specifically on a narrow range of locks. The lock is a dmg receptor. A dmg is a substance that causes a physiological response the receptor is the molecule through which it works. 

Emii Fischer s lock-and-key analogy is just 100 years old [E. Fischer, Ber. Dtsch. Chem. Ges., 27, 2985 (1894)], but the basic idea of complementariness as a factor in the formation of stable associations goes back to much earlier times. It was expressed more than 2000 years ago by Lucretius in his De Rerum Natura ... 

We have left this discussion until after description of the Eyring transition-state theory because there are many similarities. The main difference is that usually the active site pocket of an enzyme has two main geometrical attributes. First, there is the lock and key analogy, which notes that usually the entrance to the active site is stereospecific to a particular substrate molecule or a class of molecules. We see that in Figure 8.6 with catechol oxidase for substituted phenols. Much has been made of the lock-and-key concept in pharmaceutical research since that is how substrate specificity is achieved and many medicinal dmg molecules are designed with a specific shape and... 

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