Induced-fit vs. Pre-fit Models of Enzyme Catalysis
Possible Implications of the Pre-fit Model in Quantum Measurement and the Genesis of Consciousness
Sungchul Ji, Ph.D. (with ChatGPT assistance)
Emeritus Professor of Theoretical Cell Biology
Ernest Mario School of Pharmacy,
Rutgers University, Piscataway, NJ
1. Introduction
Most people familiar with biochemistry have heard of the induced-fit model of enzyme catalysis, popularized by Daniel Koshland in 1958. In this view, the enzyme changes its shape in response to binding a substrate, snugly wrapping around it to facilitate the reaction. While this was a major advance over the earlier "lock-and-key" model of Emil Fischer (1894), induced-fit alone does not fully capture the dynamical subtleties of enzyme catalysis.
In 1974, I introduced an alternative framework, the pre-fit hypothesis, which has since gained renewed significance. Unlike induced-fit, the pre-fit mechanism argues that conformational changes of enzymes precede the rapid chemistry of bond-making and bond-breaking, guided by the Generalized Franck–Condon Principle. This principle, borrowed from quantum chemistry, states that when two processes of vastly different speeds are coupled, the slower process must occur first.
This idea, published in my paper Energy and Negentropy in Enzymic Catalysis (Annals of the New York Academy of Sciences, 1974), predates by decades the conformational selection model articulated by Boehr, Nussinov, Wright, and others in the 2000s. It also opens doors to profound implications beyond biochemistry—in quantum measurement and even the emergence of consciousness.
2. Induced-fit: The Classical Paradigm
Proposed: Daniel Koshland (1958)
Core Idea: Substrate binding induces a change in enzyme shape, optimizing the catalytic site for reaction.
Strength: Explained experimental data better than Fischer’s rigid lock-and-key model.
Limitation: Suggests the enzyme’s catalytic power is fully realized after substrate binding, ignoring pre-existing conformations and timing constraints.
3. The Pre-fit Hypothesis (Ji, 1974)
Proposed: Sungchul Ji (1974)
Principle: Based on the Generalized Franck–Condon Principle (GFCP) or the Principle of Slow and Fast Processes (PSFP).
Core Idea: Enzymes must adopt the correct catalytic conformation before the chemical step can occur. The conformational transition (slow) precedes and enables the covalent rearrangement (fast).
Implication: The enzyme “pre-fits” itself into a catalytically competent state.
Corollary: All enzymatic reactions are rate-limited by conformational changes of the enzyme, not by the electronic rearrangements themselves.
This theory not only anticipates conformational flexibility but also provides a kinetic and quantum-mechanical rationale for why pre-organization is essential.
4. Conformational Selection (2000s)
Proposed: Boehr, Nussinov, Wright, and colleagues (~2006–2009).
Principle: Proteins exist in ensembles of conformations even without substrate. Binding selectively stabilizes a pre-existing complementary conformation.
Difference from Pre-fit: Rooted in thermodynamics and statistical sampling rather than kinetic precedence.
Historical Note: While conformational selection has experimental validation, the pre-fit hypothesis (1974) is an earlier, distinct theoretical framework.
5. Implications Beyond Enzymes
1) Quantum Measurement
The pre-fit principle resonates with the measurement problem in quantum mechanics. Just as the enzyme must pre-configure its conformation before catalysis, a quantum measurement device must adopt a “ready” state before interacting with a quantum system. The coupling of slow (apparatus preparation) and fast (quantum event) processes echoes the GFCP.
2) Genesis of Consciousness
The leap from enzymatic catalysis to consciousness may seem vast, but both involve coupling across scales. If consciousness arises from the interplay of fast quantum/biochemical events and slower neuronal/conformational processes, then the pre-fit mechanism could provide a general framework. Conscious experience may depend on pre-structured neural or molecular states that enable rapid, fleeting quantum events to manifest at the macroscopic, experiential level.
6. Conclusion
The history of enzyme catalysis models reveals a subtle but crucial distinction: induced-fit explains responsiveness, conformational selection explains sampling, but pre-fit explains timing and precedence. My 1974 formulation placed enzymatic catalysis in the broader context of quantum kinetics, foreshadowing later discoveries in protein dynamics.
Beyond enzymes, the pre-fit mechanism may hold keys to two of science’s greatest puzzles: the nature of quantum measurement and the origin of consciousness. By recognizing the precedence of slow structural preparation over fast dynamical events, we glimpse a unifying principle that may underlie both life and mind.
Suggested Reading:
Ji, S. (1974). Energy and Negentropy in Enzymic Catalysis. Annals of the New York Academy of Sciences, 227, 419–437.
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