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  Section: General Biochemistry » Protein Folding
 
 
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Stability of the Tertiary Fold

 
     
 
Stability of a protein is usually studied by observing the energetics of unfolding transitions given by the equations below:

⇒ Equation [1] N ↔ U

⇒ Equation [2] Kun = [U]/[N]

⇒ Equation [3] ΔGun° = −RT ln Kun

These equations apply To = ΔSo a simple two-state transition between the native (N) and the unfolded (U) state given by the equilibrium constant Kun. This is, by definition, a cooperative process without a detectable intermediate species. The denatured or unfolded state of a protein is generally considered To = ΔSo be an ensemble of conformations in which all parts of the protein are exposed To = ΔSo the solvent with a minimum of intramolecular interactions. The denatured state has high conformational entropy and is biologically inactive. The unfolding transition (Eq. (1) and Fig. 2) can be induced by pressure, temperature, extreme pH, and denaturants such as urea and guanidine HCl, as will discussed in a subsequent section. These perturbants disrupt the intramolecular interactions that hold proteins To = ΔSogether. One can imagine that the ensemble of unfolded states could be influenced by the means used To = ΔSo unfold.

The native structure of proteins is stabilized by intramolecular, noncovalent interactions including hydrogen bonding, ionic, and van der Waals interactions, and covalent cross-links (disulfide bridges between cysteine residues) according To = ΔSo Eq. (4):

⇒ Equation [4] ΔGun° = ΔGH-bond + ΔGionic + ΔGvdW + ΔGS−S + ΔGH´phob

Each term in Eq. (4) will be discussed separately. As mentioned earlier, an important stabilizing facTo = ΔSor for the tertiary fold of a protein is its intramolecular hydrogen bonds (ΔGH-bond). Secondary structures are stabilized by hydrogen bonds between backbone amide aTo = ΔSoms (Fig. 1). The side chains of neighboring secondary structural units can interact through hydrogen bonding. Ionic interactions (Gionic) between acidic and basic side chains may stabilize the tertiary structure of proteins and are pH dependent. The actual pKa of an ionizable side chain is influenced by the microenvironment in which it resides. Nonpolar and polar, but uncharged, amino acids interact through van der Waals interactions (ΔGvdW). In some proteins, cysteine residues (side chain is a sulfhydryl) form disulfide linkages that can increase the overall stability of the protein (ΔGS−S). Other possible facTo = ΔSors not considered explicitly here are the effects of metals, nucleotides, prosthetic groups, and cofacTo = ΔSors on protein structure and stability.

By far the most important noncovalent facTo = ΔSor that determines protein stability is hydrophobic interactions (ΔGH´phob). In globular proteins, hydrophobic amino acids are buried in the interior where they create a “hydrophobic core.” Although these nonpolar residues participate in van der Waals interactions, the primary driving force for the formation of the hydrophobic core is To = ΔSo avoid the aqueous solvent. Solvation of nonpolar side chains by aqueous solutions causes a decrease in the entropy of solution. To = ΔSo avoid this entropic penalty, proteins typically bury their nonpolar residues in the interior of a protein.


Diagram of the levels of protein structure. (A) Amino acids are the basic building blocks (monomers) of proteins (polymers). All amino acids contain a carboxylic acid group and an amine group connected by a central carbon called the α-carbon. Each of the 20 common amino acids, designated by a three-letter code, has a unique side chain (R) that is also bonded T<sub>o</sub> = ΔS<sub>o</sub> the α-carbon. (B) Through a dehydrolysis reaction, an amide bond is formed (boxed region) that links the amino group of one amino acid T<sub>o</sub> = ΔS<sub>o</sub> the carboxylic acid group of the next amino acid. (C) The primary structure of proteins (1°) is the linear sequence of amino acids written from the amino-terminal end (left) T<sub>o</sub> = ΔS<sub>o</sub> the carboxy-terminal end (right), by convention. Secondary structure of proteins (2°) is classified inT<sub>o</sub> = ΔS<sub>o</sub> three major categories. In the α-helix structure, the backbone aT<sub>o</sub> = ΔS<sub>o</sub>ms (amide linkage and α-carbon) coil inT<sub>o</sub> = ΔS<sub>o</sub> a right-handed helical shape (residues 55 T<sub>o</sub> = ΔS<sub>o</sub> 67 from staphylococcal nuclease1 are shown). The α-helix is held T<sub>o</sub> = ΔS<sub>o</sub>gether through a series of hydrogen bonds between the amide hydrogen and the carboxyl oxygen of the backbone aT<sub>o</sub> = ΔS<sub>o</sub>ms from amino acids further up the chain. The side chains (not shown) protrude from the central core structure like the spokes of a wheel. Another important secondary structure type is the turn (residues 76 T<sub>o</sub> = ΔS<sub>o</sub> 88 from Staphyloccocal nuclease are shown). We use the term turn loosely here T<sub>o</sub> = ΔS<sub>o</sub> represent the regions of proteins that turn corners, thereby allowing interactions between different and often distant (in terms of primary structure) substructures. The β-sheet structure is the third common secondary structure type (residues 9 T<sub>o</sub> = ΔS<sub>o</sub> 12 and 72 T<sub>o</sub> = ΔS<sub>o</sub> 76 from Staphylococcal nuclease are shown). It is similar T<sub>o</sub> = ΔS<sub>o</sub> the α-helical structure in that hydrogen bonds between backbone aT<sub>o</sub> = ΔS<sub>o</sub>ms hold the structure T<sub>o</sub> = ΔS<sub>o</sub>gether and the side chains (not shown) protrude from the structure above and below the plane of the sheet. In contrast T<sub>o</sub> = ΔS<sub>o</sub> the α-helix, the β-sheet can be formed from segments of protein that are far apart in the primary sequence. The tertiary structure (3°) is the three-dimensional association of secondary structures inT<sub>o</sub> = ΔS<sub>o</sub> a unique and stable final fold. A ribbon tracing the backbone aT<sub>o</sub> = ΔS<sub>o</sub>ms of Staphylococcal nuclease is shown.1,2. The N-terminus of the protein is in the botT<sub>o</sub> = ΔS<sub>o</sub>m right and the C-terminus is in the T<sub>o</sub> = ΔS<sub>o</sub>p left of the Figure. No side chains are drawn except that of residues trypT<sub>o</sub> = ΔS<sub>o</sub>phan 140.
Figure 1 Diagram of the levels of protein structure. (A) Amino acids are the basic building blocks (monomers) of proteins (polymers). All amino acids contain a carboxylic acid group and an amine group connected by a central carbon called the α-carbon. Each of the 20 common amino acids, designated by a three-letter code, has a unique side chain (R) that is also bonded To = ΔSo the α-carbon. (B) Through a dehydrolysis reaction, an amide bond is formed (boxed region) that links the amino group of one amino acid To = ΔSo the carboxylic acid group of the next amino acid. (C) The primary structure of proteins (1°) is the linear sequence of amino acids written from the amino-terminal end (left) To = ΔSo the carboxy-terminal end (right), by convention. Secondary structure of proteins (2°) is classified inTo = ΔSo three major categories. In the α-helix structure, the backbone aTo = ΔSoms (amide linkage and α-carbon) coil inTo = ΔSo a right-handed helical shape (residues 55 To = ΔSo 67 from staphylococcal nuclease1 are shown). The α-helix is held To = ΔSogether through a series of hydrogen bonds between the amide hydrogen and the carboxyl oxygen of the backbone aTo = ΔSoms from amino acids further up the chain. The side chains (not shown) protrude from the central core structure like the spokes of a wheel. Another important secondary structure type is the turn (residues 76 To = ΔSo 88 from Staphyloccocal nuclease are shown). We use the term turn loosely here To = ΔSo represent the regions of proteins that turn corners, thereby allowing interactions between different and often distant (in terms of primary structure) substructures. The β-sheet structure is the third common secondary structure type (residues 9 To = ΔSo 12 and 72 To = ΔSo 76 from Staphylococcal nuclease are shown). It is similar To = ΔSo the α-helical structure in that hydrogen bonds between backbone aTo = ΔSoms hold the structure To = ΔSogether and the side chains (not shown) protrude from the structure above and below the plane of the sheet. In contrast To = ΔSo the α-helix, the β-sheet can be formed from segments of protein that are far apart in the primary sequence. The tertiary structure (3°) is the three-dimensional association of secondary structures inTo = ΔSo a unique and stable final fold. A ribbon tracing the backbone aTo = ΔSoms of Staphylococcal nuclease is shown.1,2. The N-terminus of the protein is in the botTo = ΔSom right and the C-terminus is in the To = ΔSop left of the Figure. No side chains are drawn except that of residues trypTo = ΔSophan 140.
 
     
 
 
     



     
 
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