Overview of Protein Structure:- A Protein’s Conformation Is Stabilized Largely by Weak Interactions

In the context of protein structure, the term stability can be defined as the tendency to maintain a native con formation. Native proteins are only marginally stable; the Gseparating the folded and unfolded states in typical proteins under physiological conditions is in the range of only 20 to 65 kJ/mol. A given polypeptide chain can theoretically assume countless different conformations, and as a result the unfolded state of a protein is characterized by a high degree of conformational entropy. This entropy, and the hydrogen-bonding interactions of many groups in the polypeptide chain with sol vent (water), tend to maintain the unfolded state. The chemical interactions that counteract these effects and stabilize the native conformation include disulfide bonds and the weak (noncovalent) interactions described in Chapter 2: hydrogen bonds, and hydrophobic and ionic interactions. An appreciation of the role of these weak interactions is especially important to our understanding of how polypeptide chains fold into specific secondary and tertiary structures, and how they combine with other polypeptides to form quaternary structures. About 200 to 460 kJ/mol are required to break a sin gle covalent bond, whereas weak interactions can be disrupted by a mere 4 to 30 kJ/mol. Individual covalent bonds that contribute to the native conformations of proteins, such as disulfide bonds linking separate parts of a single polypeptide chain, are clearly much stronger than individual weak interactions. Yet, because they are so numerous, it is weak interactions that predominate as a stabilizing force in protein structure. In general, the protein conformation with the lowest free energy (that is, the most stable conformation) is the one with the maximum number of weak interactions. The stability of a protein is not simply the sum of the free energies of formation of the many weak inter actions within it. Every hydrogen-bonding group in a folded polypeptide chain was hydrogen-bonded to water prior to folding, and for every hydrogen bond formed in a protein, a hydrogen bond (of similar strength) between the same group and water was broken. The net stability contributed by a given weak interaction, or the difference in free energies of the folded and unfolded states, may be close to zero. We must therefore look elsewhere to explain why the native conformation of a protein is favored. We find that the contribution of weak interactions to protein stability can be understood in terms of the properties of water. Pure water contains a network of hydrogen-bonded H₂O molecules. No other molecule has the hydrogen-bonding potential of water, and other molecules present in an aqueous solution disrupt the hydrogen bonding of water. When water sur rounds a hydrophobic molecule, the optimal arrange ment of hydrogen bonds results in a highly structured shell, or solvation layer, of water in the immediate vicinity. The increased order of the water molecules in the solvation layer correlates with an unfavorable de crease in the entropy of the water. However, when non polar groups are clustered together, there is a decrease in the extent of the solvation layer because each group no longer presents its entire surface to the solution. The result is a favorable increase in entropy. As described in Chapter 2, this entropy term is the major thermodynamic driving force for the association of hydrophobic groups in aqueous solution. Hydrophobic amino acid side chains therefore tend to be clustered in a protein’s interior, away from water. Under physiological conditions, the formation of hydrogen bonds and ionic interactions in a protein is driven largely by this same entropic effect. Polar groups can generally form hydrogen bonds with water and hence are soluble in water. However, the number of hydrogen bonds per unit mass is generally greater for pure water than for any other liquid or solution, and there are limits to the solubility of even the most polar molecules as their presence causes a net decrease in hydro gen bonding per unit mass. Therefore, a solvation shell of structured water will also form to some extent around polar molecules. Even though the energy of formation of an intramolecular hydrogen bond or ionic interaction between two polar groups in a macromolecule is largely canceled out by the elimination of such interactions between the same groups and water, the release of structured water when the intramolecular interaction is formed provides an entropic driving force for folding. Most of the net change in free energy that occurs when weak interactions are formed within a protein is therefore derived from the increased entropy in the sur rounding aqueous solution resulting from the burial of hydrophobic surfaces. This more than counterbalances the large loss of conformational entropy as a polypep tide is constrained into a single folded conformation. Hydrophobic interactions are clearly important in stabilizing a protein conformation; the interior of a pro tein is generally a densely packed core of hydrophobic amino acid side chains. It is also important that any po lar or charged groups in the protein interior have suit able partners for hydrogen bonding or ionic interactions. One hydrogen bond seems to contribute little to the stability of a native structure, but the presence of hydrogen-bonding or charged groups without partners in the hydrophobic core of a protein can be so destabilizing that conformations containing these groups are often thermodynamically untenable. The favorable free energy change realized by combining such a group with a partner in the surrounding solution can be greater than the difference in free energy between the folded and unfolded states. In addition, hydrogen bonds between groups in proteins form cooperatively. Formation of one hydrogen bond facilitates the formation of additional hydrogen bonds. The overall contribution of hydrogen bonds and other noncovalent interactions to the stabilization of protein conformation is still being evaluated. The interaction of oppositely charged groups that form an ion pair (salt bridge) may also have a stabilizing effect on one or more native conformations of some proteins. Most of the structural patterns outlined in this chapter reflect two simple rules: (1) hydrophobic residues are largely buried in the protein interior, away from water; and (2) the number of hydrogen bonds within the protein is maximized. Insoluble proteins and proteins within membranes (which we examine in Chapter 11) follow somewhat different rules because of their function or their environment, but weak interactions are still critical structural elements.

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مواضيع ذات صلة

Overview of Protein Structure:- The Peptide Bond Is Rigid and Planar

Protein Sequences and Evolution:- Protein Sequences Can Elucidate the History of Life on Earth

The Covalent Structure of Proteins:- Amino Acid Sequences Provide Important Biochemical Information

The Covalent Structure of Proteins:- Small Peptides and Proteins Can Be Chemically Synthesized

The Covalent Structure of Proteins:- Amino Acid Sequences Can Also Be Deduced by Other Methods

The Covalent Structure of Proteins:-Large Proteins Must Be Sequenced in Smaller Segments

The Covalent Structure of Proteins:- Short Polypeptides Are Sequenced Using Automated Procedures

The Covalent Structure of Proteins:-The Amino Acid Sequences of Millions of Proteins Have Been Determined

The Covalent Structure of Proteins:-The Function of a Protein Depends on Its Amino Acid Sequence

Working with Proteins:- Unseparated Proteins Can Be Quantified

Working with Proteins:- Proteins Can Be Separated and Characterized by Electrophoresis

Working with Proteins:- Proteins Can Be Separated and Purified