BIOCHEMISTRY - L. Stryer - 1984

VOLUME 1

PART I. CONFORMATION AND DYNAMICS

CHAPTER 2. PRINCIPLES OF PROTEIN STRUCTURE AND FUNCTION

2.13. The Folding of Protein Molecules Occurs Through the Association of α-Helices and Pleated β-Sheets

How is harmony achieved when an extended polypeptide chain folds into a compact protein molecule? A priori, one possibility is that all possible Conformations are sampled until the energetically most favorable form is selected. How long would such a random search for a stable Structure take? Let us consider, for example, a small protein consisting of 100 amino acid residues.

If each residue can adopt 3 different conformations, the total number of possible structures would be 3¹⁰⁰, or 5 • 10⁴⁷. If the conversion from one structure to another takes 10^-13 s, the total time required to find the optimal conformation would be 5 • 10⁴⁷ • 10^-13 s, i.e., 5 • 10³⁴ s, or 1.6 • 10²⁷ years! Note that this time is a minimum, since the true number of possible conformations per amino acid residue is higher than three, and the time required for a conformational transition likely exceeds 10^-13 s. It is entirely obvious that even for a small protein, the time required to select the energetically optimal conformation by random sampling of all possibilities is far too long.

How is it, then, that Proteins attain their correct conformation within a matter of seconds or minutes? The answer is not yet known, but a rather compelling hypothesis suggests that small segments of Secondary structure play a crucial role in this process. According to the proposed model, short stretches (~ 15 amino acid residues) of the extended polypeptide chain form short-lived structures: α-helices or β-sheets. These intermediate structures approach one another through diffusion and stabilize each other by forming complexes (Fig. 2.48). Suppose that two α-helices, two β-sheets, or an α-Helix and a β-sheet have come together. The resulting complexes, designated αα, ββ, or αβ and referred to as nucleation units, subsequently act as centers that stabilize other protruding elements of secondary structure. This model is supported by several lines of experimental evidence. First, the ability of a polypeptide to form a correct secondary structure depends largely on its Amino Acid Composition. For instance, glutamate, Methionine, Alanine, and leucine residues promote the formation of α-helices, whereas valine, isoleucine, and Tyrosine residues enhance the formation of β-sheets. Second, the transition from a random coil to an α-helix occurs in less than one microsecond. Consequently, short segments of secondary structure can form very rapidly. Third, the postulated nucleation units (αα, ββ, and αβ complexes) essentially represent the fundamental Building Blocks of Cell/13.html">Protein Structure. The challenge today is to directly detect and identify the short-lived intermediates formed during the specific folding of a polypeptide chain, thereby reconstructing the pathway that leads to the Formation of the functionally active protein structure.

Class="center">Fig. 2.48. Proposed Stages of Protein folding. Two segments within the extended polypeptide chain transiently adopt an α-helical structure. Subsequently, both helices are stabilized through the formation of a complex between these regions