1. From lock and key model to induced fit model
Understanding how science works
Victor Lau
CUHK

2. What you think it may be like that
Science model
Explain to students that they have just used a science model to explain the enzyme action.
What you observed
What you think it may be like that

3. Science model
A model in science is a simplified description and explanation of the natural process.
Sometimes model is used the same as theory in science.
The development of science model needs a little of imagination: You had not really seen a substrate binding to the enzyme!

4. In 1894, Fischer first used lock and key to explain the action of enzymes - lock and key model
The key (substrate) fits in the key hole (active site) of the lock (enzyme). This model illustrates the specificity of enzyme actions since one key can only open one specific lock. The specificity of the key-lock is a result of their complementary shapes, which is also a crucial feature between substrate and active site. Fischer likened the enzyme to a lock and the substrate to a key since enzymes are often larger than substrates and its active site is always hidden inside the enzyme molecule. But some people later claim that enzyme is better likened to the key since it is not changed in the action. These arguments show that models often have limitations in showing the real natural phenomena. Above all, adhering to Fischer’s original idea would be more appropriate.
Group discussion
How is lock-key similar to enzyme action?
Would you liken enzyme to a lock or a key? Why?

5. Lock-key model is a science model to explain the specificity of enzyme action.
However, lock-key model does not truly represent the real enzyme action, which would be more complex.
Fischer was creative to think of this model as he never directly saw how enzyme works!

6. Models ? Do not mix up science model with physical model.
Scientific model is a concept, which can be represented in physical model, diagrams, mathematical formula, and even words.
Lock and key model represented by physical model
Lock and key model represented by diagram

7. Problems with lock and key modelX Z
Which substrate can bind with the enzyme?
Move the substrate to the active site of the enzyme. All of them can fit to it. But it is only X that can be catalyzed into product.
Scientists found some molecules tightly bound to the active site of an enzyme but not catalyzed into product. This cannot be explained by the lock and key model!
This further illustrates why model is a “simplified” description of natural events.
All can tightly bind with the enzyme, but only X will be catalyzed into product! Why?

8. A new model - induced fit model
In 1958, Koshland proposed an induced fit model to account for the problems.
reaction !
The binding of the substrate on the active site “induce” a change in shape of the enzyme. The catalytic groups A and B of the enzyme are brought to the correct locations to bring about the reaction.

9. Catalytic groups A and B are brought to the right locations to catalyze the substrate into products.
This model can explain why some molecules that are tightly bound to the active site but not catalyzed. It is because the binding cannot “induce” a proper change in the shape of the enzyme so that the substrate can be catalyzed into product.
Catalytic groups A and B cannot go to the right locations. So there is no catalysis of the substrate.

10. Induced fit model
Koshland likened the model to a hand in a glove. Why??
How is this model different from the lock-key model?
A glove only fits perfectly with and takes the shape of a hand after the hand completely slips into the glove. It is like the enzyme (glove) which only fits perfectly to the substrate (hand) after the substrate binds to the enzyme. The insertion of the hand causes a change in shape of the glove, which is akin to the shape change induced by enzyme-substrate binding.
In the lock-key model, enzyme is rigid with fixed shape, but enzyme is flexible in the induced fit model.

11. Try to use the physical model provided to explain the induced fit model.
Give some time for groups to discuss. Then invite some to show the class how this model can represent the induced fit model.
- Open the notch of the enzyme at the active site
Bind the two substrates to the active site, but they cannot react as they are not in the right positions.
Close the notch so that the two substrates are in contact and can bind with each other. This shows the change in shape of the enzyme induced by the binding of the substrate.

12. Evidence for induced fit model?
Koshland needed to provide evidence to convince other scientists to accept this new model!
According to the hypothesis that enzyme can change its shape when bound by a substrate, he predicted that some chemical groups may be exposed by the binding. This would not be possible for a “rigid” enzyme in the lock-key model.

13. Initial evidence for induced fit model
SH group hidden
SH group is exposed after binding

14. Is the evidence convincing?
“ The theory of Emil Fischer was deep in the hearts of scientists and journal editors, so I had great difficulty getting the original ideas published or convincing skeptics... “ Koshland 1994
Group discussion
Scientists strike to be objective and rational, that is, making a conclusion based on evidence. But in science, evidence for a new theory is often insufficient and conflicting at the beginning. It is therefore rational to be skeptical about the new evidence and new theory. Nonetheless, some scientists may also “subjectively” hold on to the “old” theory they believe - they are human beings after all.
Are scientists all objective and rational?

15. More evidence Other scientists “joined in” to provide more evidence.
“ The findings from modern X-ray crystallography that essentially all enzymes undergo conformational changes induced by substrate binding has made the induced fit theory universally accepted in textbooks and by scientists.” Koshland 1994
The only criteria for the acceptance of a theory in science is that it is supported by sufficient empirical evidence. So, even Koshland’s idea was initially rejected, it was finally well accepted when evidence was enough. It shows that scientists are rational in general and science is empirical.
Evidence does not come from one scientist, but many many! Scientists do not work alone, but as a community. Koshland published his findings so other scientists could join in to provide more evidence (or, on the contrary, proved Koshland was wrong!). Findings have to be shared and checked by all other scientists, which is a norm in science community. Only pseudoscience would claim their findings are a secret!
Sometimes strong evidence for a new theory needs to wait for a breakthrough in technology. Only after X ray crystallography was developed can scientists directly “see” the shapes of proteins. It provided the strongest direct evidence to the induced fit theory.
Group discussion
Why other scientists wanted and could “join in” ?
What made the induced fit model universally accepted in the end?

16. A journey of scientific discovery
Fischer put forward the lock and key model. It was widely accepted for nearly 100 years.
1958 – Koshland proposed induced fit model
1970s – Induced fit model widely accepted
Group discussion
The induced fit model might also be found wrong when more evidence about enzymes appears in the future, so does all science knowledge – science is tentative!
But, modern science rarely overthrows a well established theory, but extends and modifies it. Take the example of the lock-key model, which was not discarded completely but extended by the induced fit model. The development of the induced fit model has actually based on many concepts from the lock-key model, such as the complementarity and the transition state of enzyme action. So, in that sense, science is progressing toward a better understanding of nature, rather than replacing something wrong.
Sometimes science does undergo drastic change –from earth-centered to sun centered universe, from Newtonian mechanics to Einstein’s relativity, from creationism to Darwin’s theory of evolution, from blending theory to Mendelian inheritance. These are called paradigm shift in Kuhn’s term. However, most of these paradigm shifts are from prescience to modern science. Modern biological science does not really have many paradigm shift.
Despite that science does change, the majority of science knowledge is rather stable and durable. So it is still the most reliable knowledge about nature. We are applying science in every aspect of our modern lives. If science is not reliable, the whole world would become a chaos! So we should not undermine the whole of science by simply looking at the wrong paths of science during its progress. But, on the other hand, we also should not treat the present science knowledge as absolute truth.
Do you think the induced fit model may be also found wrong in the future?
If science knowledge can change over time, is it reliable? Should we still believe in science?

17. Reference
Koshland, D. E. (1994). The Key-Lock Theory and the Induced Fit Theory. Angew. Chem. Inl. Ed. Engl. 33,
Koshland, D. E. (2004). Crazy, but correct. Nature, 432