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22

Biological Signalling

levels of organization. They may be considered as mechanical devices with specific

mechanical degrees of freedom. ¹¹

Generically we can suppose that we are dealing with the effect of some molecule

from the environment, which we call the “ligand”, on a receptor molecule. The

general mechanism of recognition and actuation, which also applies to the action

of enzymes (in which case the ligand is usually called the “substrate”—typically

a molecule that is to be decomposed in some fashion, or joined to another one,

in all cases involving breaking of bonds—and the receptor is the enzyme), can be

decomposed into 4 steps:

1. Formation of the ligand–receptor complex. This involves binding to the active

site of the receptor, changing its conformation locally and creating strain between

the active site and the rest of the receptor molecule; overall it is now out of

equilibrium;

2. Slow relaxation of the ligand–receptor complex to a new equilibrium conforma-

tion, coupled to appropriate changes elsewhere in the receptor molecule, continu-

ing the chain of transduction (in the case of an enzyme, this would be the substrate

right arrow→product transformation);

3. Dismemberment of the ligand–receptor complex (release of the product in the

case of the enzyme reaction);

4. Finally, slow relaxation of receptor back to the initial equilibrium state of a free

macromolecule (free in the sense of uncomplexed—a transmembrane receptor

would, of course, remain embedded in the membrane).

In step 1, the free energy change is

Delta upper G 1 equals Delta upper G 1 Superscript left parenthesis active site right parenthesis Baseline plus Delta upper G 1 Superscript left parenthesis rest of molecule right parenthesis Baseline semicolonΔG1 = ΔG^{(active site)}

1

+ ΔG^{(rest of molecule)}

1

;

(22.1)

the first term of the right is less than zero (i.e., happens spontaneously, driven by the

energy released from ligand–receptor bond formation), whereas the second term is

greater than zero; evidently the overall free energy change of step 1 must be less than

zero.

In step 2, the slow conformation relaxation has Delta upper G 2 Superscript left parenthesis normal r normal e normal c normal e normal p normal t normal o normal r right parenthesis Baseline less than 0ΔG^(receptor)

2

< 0, which provides

the free energy to drive the transduction, withDelta upper G 1 Superscript left parenthesis normal t normal r normal a normal n normal s normal d normal u normal c normal t normal i normal o normal n right parenthesis Baseline greater than 0ΔG^{(transduction)}

1

> 0, andStartAbsoluteValue Delta upper G 2 Superscript left parenthesis normal r normal e normal c normal e normal p normal t normal o normal r right parenthesis Baseline EndAbsoluteValue greater than StartAbsoluteValue Delta upper G 1 Superscript left parenthesis normal t normal r normal a normal n normal s normal d normal u normal c normal t normal i normal o normal n right parenthesis Baseline EndAbsoluteValue|ΔG^(receptor)

2

| >

|ΔG^{(transduction)}

1

|.

In step 3, release of the ligand from the binding site requires free energy

(Delta upper G 3 Superscript left parenthesis active site right parenthesis Baseline greater than 0ΔG^{(active site)}

3

> 0), which is provided by some molecular motions in the rest of the

molecule, again with overall Delta upper G 3 less than 0ΔG3 < 0, and ending up with conformational strain.

The final step 4 then happens spontaneously (Delta upper G 4 less than 0ΔG4 < 0).

11 Blumenfeld (1981).