Cell Language Theory, The: Connecting Mind And Matter

The Bhopalator 95

“6x9” b2861 The Cell Language Theory: Connecting Mind and Matter

common native structure. In short, the paradigm shift is from individual

intermediate conformational isomers of a protein to an ensemble of them,

on the one hand, and from a single folding pathway to an ensemble of

folding pathways (down the folding funnel), on the other hand.

Leopold et al. [187] characterize the “protein, folding funnel” as

follows:

... a kinetic mechanism for understanding the self-organizing principle

of the sequence–structure relationship. This concept follows from a

few general considerations. (i) Proteins fold from a random state by

collapsing and reconfiguring (i.e., mainly conformationally rearrang-

ing polypeptides without breaking or forming covalent bonds; my addi-

tion), (ii) reconfiguration occurs diffusively (i.e., as a consequence of

Brownian motions of proteins: my addition) and follows a general drift

from higher energy to lower energy conformations, and (iii) reconfigu-

ration occurs between conformations that are geometrically similar —

i.e., globular interconversions are energetically prohibitive after

collapse — so local interconversions alone are considered. We define

the folding funnel as a collection of geometrically similar collapsed

structures, one of which is thermodynamically stable with respect

to the rest, though not necessarily with respect to the whole conforma-

tion space.... (3.22)

Just as water flows down a funnel, higher energy conformers of a

denatured protein are thought to “flow” down the folding funnel toward

lower energy conformers through several conformational states (“molten

globular states”, “transition state”, “glass transition”, “discrete folding

intermediates”, etc.) to the final native structure. The movement of protein

conformers down the folding funnel entails two types of thermodynamic

changes: (i) energy decrease due to downward movement and (ii) entropy

decrease due to the narrowing of the funnel width, reflecting increasing

conformational constraints (i.e., as conformations of a protein become

more compact to minimize energy, the conformational motions of proteins

become less free and confined to an increasingly smaller volume, leading

to a decrease in entropy).

Since protein folding is ultimately driven by Gibbs free energy

changes, we have ∆G = Gfinal – Ginitial = ∆E + ∆V – T∆S (where ∆ denotes

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