To characterize the nature of protein-protein interactions, three different models have been proposed. Emil Fischer first suggested the lock and key paradigm, which depicts inflexible interactions. Here, the shapes of the two interaction interfaces are complimentary, and binding induces relatively minimal conformational change. Conversely, the induced fit model accounts for conformational alterations that occur during binding and enable interactions between proteins with various degrees of shape complementarity in the unbound state.
An enzyme alters its conformation when it binds a ligand, just like a glove changes shape when a hand slides inside it. A weak initial complex forms, followed by intermediates that progressively rearrange to make new interactions until the final high-affinity state is attained. The conformational selection model employs the dynamic structure of proteins where each interaction partner will experience several conformational states, but only specific states will be able to interact.
What is Induced Fit Model?
The lock-and-key theory proposed 100 years ago is expanded by this induced fit theory. The new theory put forth by D. E. Koshland, Jr. in 1958 explains regulatory and cooperative effects and also introduces some new specificity concepts. According to this hypothesis, an enzyme’s active site is not architecturally ideal for substrate binding when it is in the unbound state (i.e., not bound to the substrate).
Several factors influence the structural configuration of the active site in enzymes, such as binding to cofactors or coenzymes, pH, ionic strength, temperature, enzymatic modification like glycosylation, phosphorylation, etc., and lipid binding. An active site is the most important binding site on the surface of enzymes specifically designed to interact with other molecules. The catalytic site and substrate binding site constitute the active site, where the former has a set of two to six amino acid residues that facilitate the catalytic reaction.
At the same time, the latter serves to recognize the ligand upon which the enzyme acts. This active site has a fluid structure that gets altered concerning the alteration in the enzyme’s environment or substrate binding.
Thus, the name induced fit model is termed so for the induced small change of active site of an enzyme such that substrate can achieve optimal fit. This configuration change catalyzes the reaction, meanwhile lowering the activation energy barrier and resulting in an increase in the overall rate of the reaction.
In the induced fit model, both the substrate enzyme’s active site undergoes conformational changes up until the substrate is fully attached to the enzyme. At this time, the final shape and charge are established. This prompts the enzyme to start acting catalytically. Initially, the enzyme’s active site and substrate are not exactly complementary.
Supporting findings that led to widely accepted induced fit model
Researchers have realized that proteins are not solid structures. Multiple sections of an enzyme molecule were demonstrated to move throughout experiments in reaction to the environment. Most of these movements were minor, but some were more important. When the substrate was attached to the enzyme, the motions became more pronounced.
- The substrate and active site are not perfectly complementary before binding.
- The active site deforms shape and conforms to the substrate upon binding.
- The structural modification in the catalytic site was supported by X-ray diffraction and optical rotational analyses.
- It explains how the catalytic group stays apart, preventing non-substrates from being processed.
- It describes how the transition state forms before the conversion of substrates to products.
How does the induced fit model work?
- The suitable substrate arrives at the active site of an enzyme where it doesn’t fit perfectly. Many of the same forces that keep tertiary structure in check during peptide chain folding also pull the substrate into the active site.
- Substrate molecules are drawn to and bound via electrostatic interactions, hydrogen bonds, and hydrophobic interactions.
- Enzymes don’t necessarily bind just to one substrate. Allosteric binding of regulating molecules, either activator or inhibitor, alters the conformation of an enzyme that affects its ability to catalyze reactions.
- The amino acid side chains that make up the active site are molded into appropriate positions such that the catalytic function of the enzyme gets activated.
- The active site changes its conformation until the substrate makes a tight bond with the enzyme, forming the enzyme-substrate complex. The final shape and charge distribution are determined at the point where the substrate is completely bound to the substrate.
- The catalytic groups at the active site interact with the substrate to produce two or more products.
- The products detach from the enzyme’s surface, allowing it to reverse to normal shape and further repeat the process.
- Nonsubstrate molecules that are too big or too small change the structure of the enzyme, leading to a misalignment of the catalytic groups; despite being drawn to the active site, these molecules are unable to catalyze reactions.
The induced fit model shed light on the following points:
- The exact orientation of catalytic groups determines enzyme function.
- The substrate results in a significant change in the three-dimensional connection of the amino acids at the active site of the enzyme.
- The alterations in protein structure brought upon by the substrate will position the catalytic groups in the correct alignment, whereas a nonsubstrate won’t.
Advantages of Induced Fit Model over Lock and Key Model
This hypothesis provides the following two hypotheses:
- It illustrates the wide specificity of enzymes. For example, a variety of lipids can bind to lipase enzymes. for substrates.
- It outlines the possible causes of catalysis, i.e., the bonds in the substrate are stressed by the conformational change, boosting reactivity.
Limitations of Induced fit model
- The chemistry of catalytic reactions is not taken into consideration. Several chemical factors such as electrostatic interactions, the potential presence of cofactors, and the presence of proton donors and receptors are associated with catalysis.
- This model cannot fully describe conformational changes for extremely flexible proteins, including backbone collective movements, domain rearrangements, and disorder-to-order transition.
- Laddach, A., Chung, S. S., & Fraternali, F. (Eds.). (2019). Prediction of Protein-Protein Interactions: Looking Through the Kaleidoscope. Academic Press.
- Koshland, D.E., Jr. (1995), The Key–Lock Theory and the Induced Fit Theory. Angew. Chem. Int. Ed. Engl., 33: 2375-2378. https://doi.org/10.1002/anie.199423751