Forces Stabilizing Protein Structure determines the native, folded structure of the protein means the native structure of protein is dictated by several factors like interactions with solvent molecules (normally water), the pH and ionic composition of the solvent, and most important, the sequence of the protein. Several different kinds of noncovalent interactions are of vital importance in protein structure. Hydrogen bonds, hydrophobic interactions, electrostatic bonds, and van der Waals forces are all noncovalent in nature. Protein structures are governed primarily by hydrophobic effects and, to a lesser extent, by interactions between polar residues and other types of bonds. The stabilization free energies afforded by each of these interactions may be highly dependent on the local environment within the protein, but certain generalizations can still be made.
Table of Contents
- Forces Stabilizing Protein Structure
Forces Stabilizing Protein Structure
The important forces stabilizing protein structure are as follows
Hydrophobic bonds, is a very important driving force for protein folding and can be considered as main forces stabilizing protein structure. In this interaction, nonpolar side chains of amino acids prefer to interact with each other or cluster in a non-polar environment rather than to intercalate in a polar solvent like water. The formation of hydrophobic bonds minimizes the interaction of non-polar residues with water and is therefore highly favorable. Such clustering is entropically driven. Therefore, a polypeptide with hydrophilic and hydrophobic residues will spontaneously adopt a configuration in which the hydrophobic residues are not exposed to water. This configuration can be achieved either by sitting in a lipid bilayer or by adopting a globular shape in which the hydrophobic residues are clustered in the center or interior core of the protein. The hydrophobic interaction within non polar amino acids is one of the largest determinants of protein structure. Most secondary structural elements have an amphipathic nature, one hydrophobic side and one hydrophilic side. If the hydropathy of a side chain is greater (see Hopp Woods), it will more likely occupy the interior of a protein and vice versa. Hydropathy values are good predictors that which portions of a polypeptide chain must reside inside a protein, or should be out of contact with the aqueous solvent, and which portions must be outside.
Hydrogen bonds are linked when a pair of nucleophilic atoms like oxygen and nitrogen shares a hydrogen between them. Hydrogen bonds are usually formed wherever possible within a given protein structure by atoms of the peptide backbone. Additionally, side chains located on the protein surface are capable of forming H bonds primarily with the water solvent. H-bonds are directional and their strength declines as the angle changes. Although each individual hydrogen bond contribute almost an average of only about 12 kJ/mol in stabilization energy for the protein structure but the total number of H bonds occur in the protein is extremely large. Hydrogen bonds actually do not, in general, contribute to the net stabilization energy of proteins because the same group that forms hydrogen bond to each other in a native protein structure, can hydrogen bond to water in the denatured state of proteins. It is important to note that hydrogen bonds formation are extremely crucial because of their directionality, they can control and limit the geometry of the interactions between side-chains. These patterns of hydrogen bonding regarding controlling directionality between the carboxyl groups and the amino groups in the peptide backbone give rise to alpha helix and beta strand conformations.
The electrostatic attraction of positively and negatively charged side chains can form ion pair or salt bridge that helps in stabilization of secondary and tertiary structures. Amino acid side chains at the NH2-terminal can carry positive charges, as in the case of lysine, arginine, and histidine, while amino acid side chains at the COOH-terminal residues can carry negative charges as in aspartate and glutamate. Charged residues are generally located on the protein surface, and interact mainly with the water solvent. The main point that arises with the above discussion is that it is energetically unfavorable for an ionized residue to be located in the hydrophobic or interior core of the protein. Therefore, these interactions become important for protein stability. The electrostatic interaction is quite strong, and depends on two means, one is the distance between the charged atoms and the other is that it also depends heavily on the dielectric constant of the medium in which the protein is dissolved. It is strongest in a vacuum, weaker in water and at elevated salt solutions. Water and ions can shield electrostatic interactions that lead in reduction of both their strength and distance.
Van der Waals Interactions
These are weakest of all noncovalent forces and are non-directional. These forces result from the attraction of one atoms nucleus for the electrons of another atom in a non-covalent form. No sharing of orbitals occur. Van der Waals interactions occur at distances between 3 and 4 Å and they are very weak beyond 5Å. Importantly, electron repulsion prevents atoms from getting much closer than 3Å. They are very weak but by the additive effect of many such interactions significant energy of stabilization can be obtained in the central hydrophobic core of proteins. For example, pancreatic ribonuclease A, hen egg white lysozyme, horse heart cytochrome c, and sperm whale myoglobin, shows that van der waals interactions among tightly packed groups in the interior of the protein are a major contribution to protein stability. Note: Weakest force stabilizing protein
This is the major force stabilizing protein which are extracellular. Extracellular proteins often have disulfide bonds between specific cysteine residues. But intracellular proteins lack or have very rare disulfide bonds because the cytoplasm consists of a reducing environment. Most disulfide bonds occur in proteins that are secreted from the cell into the more oxidizing extracellular environment like endoplasmic reticulum. The relatively hostile extracellular world (e.g., uncontrolled temperature and pH) apparently requires the additional structural constraints conferred by disulfide bonds. These are covalent bonds, and they tend to lock the molecule into its conformation. Although relatively few proteins contain disulfide bonds, those that do are more stable and are therefore easy to purify and study. For this reason many of the first proteins studied in detail, such as the digestive enzymes chymotrypsin and ribonuclease and the bacterial cell wall degrading enzyme lysozyme, have disulfide bonds.
Dipole moments are formed by pairs of charges separated by a larger distance than permitting a salt- or ion bridge as in electrostatic interactions. The dipole moment gives rise to an electric field along the entire length of a structural element. The alpha helix is known to carry a partial negative charge at its C-terminus and a positive charge at its N-terminus. In order to help neutralize this charge distribution, alpha helices often have acidic residues near their N-terminus and a basic residue near their C-terminus. Dipole moments therefore are most often used by proteins to attract and position charged substrates and products.