Conformational Changes in Proteins - IIIa
A paper a few years ago in Science [Science, 2006, 313, 1638] suggests another way of looking at conformational changes taking place in enzymes on substrate binding.
- Proteins possess an energy corresponding to the temperature at which they function
- Therefore the conformations of all proteins constantly fluctuate on timescales of ps to ms
- The fluctuations provide equilibria between conformations (that is, a Boltzman distribution) of not dramatically different energies, with modest barriers between them
- Evolution has channeled these initially random fluctuations into productive events
- That is, these motions may push the unbound states of enzymes into conformations closely resembling the bound states
| A Free-Energy Channel Model for Enzyme Behavior |
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- State A is the free state, in equilibrium with two other conformations
- One of those other conformations resembles the bound state closely; binding of the ligand shifts the equilibrium in this direction (B)
- The third state is the catalytic state, again previously accessed by the random thermal motions (C)
- Release of product from C allows the fluctuations to return the enzyme to A
Chemical shift perturbation and relaxation time measurements were used to investigate the reaction of dihydrofolate reductase. which uses NADPH to reduce dihydrofolate to tetrahydrofolate:
| The Dynamic Landscape of Dihydrofolate Reductase Activity |
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The relaxation time measurements detect higher energy conformations in equilibrium with each intermediate in the catalytic cycle.
In EVERY case, the higher energy conformations strongly resemble the ground state conformations of adjacent intermediates.
That is, the random thermal motions of each state of the enzyme sample the conformations required for prior and subsequent steps of the catalytic cycle!
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