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interactions between immediately adjacent atoms.
• These non-covalent forces result from the attraction of one atoms nucleus for the electrons of another atom in a non-covalent form (no sharing of orbitals).
• Van der Waals interactions are non-directional and very weak.
• Significant stabilization can be obtained in the central hydrophobic core of proteins by the additive effect of many such interactions. |
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• The hydrophobic force is a negative non-covalent force.
• The presence of hydrophobic side chains in aqueous solution induces the formation of structured water.
• This reduction in entropy of the water molecules is a very unfavorable resulting in a strong force to keep hydrophobic side chains buried in the interior of the protein.
• The hydrophobic force is one of the largest determinants of protein structure.
• Most secondary structural elements have an amphipathic nature, one hydrophobic side and one hydrophilic side because the structure lies on the surface of the protein. |
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• The attraction of oppositely charged side chains can form salt-bridges which stabilize secondary and tertiary structures.
• The electrostatic force is quite strong and depends heavily on the dielectric constant of the medium in which the protein is dissolved. |
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• Dipole moments are caused by pairs of charges separated by a larger distance than permitting a salt- or ion bridge.
• The dipole moment can give rise to an electric field along the entire length of a structural element and are often used by proteins to attract and position charged substrates and products.
• The peptide chain naturally has a dipole moment because the N-terminus carries about 1/2 a positive charge and the C-terminus carries about 1/2 unit of negative charge.
• The alpha-helix is known to carry a partial negative charge at its C-terminus and an positive charge at its N-terminus. |
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• Hydrogen bonds occur when a pair of nucleophilic atoms such as oxygen and nitrogen share a hydrogen between them.
• The hydrogen may be covalently attached to either nucleophilic atom (the H-bond donor) and shared with the other atom (the H-bond receptor).
• H-bonds are directional and extremely important in controlling the geometry of the interactions between side-chains. |
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| • The major properties of the covalent bonds hold proteins together are their bond distances and bond angles. |
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| • Model proteins-hemoglobin and myoglobin comparison |
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o Hemoglobin and myoglobin represent two O2-transport proteins that have been extensively studied in terms of both their structures and functions. The heme proteins myoglobin and hemoglobin maintain a supply of oxygen essential for oxidative metabolism. Myoglobin, a monomeric protein of red muscle, stores oxygen as a reserve against oxygen deprivation. Hemoglobin, a tetrameric protein of erythrocytes, transports O2 to the tissues and returns CO2 and protons to the lungs. Both are globular proteins that serve as models with which to illustrate important structure/function relationships.
o The secondary-tertiary structure of the subunits of hemoglobin resembles myoglobin. However, the tetrameric structure of hemoglobin permits cooperative interactions that are central to its function. For example, 2,3-bisphosphoglycerate (BPG) promotes the efficient release of O2 by stabilizing the quaternary structure of deoxyhemoglobin. Hemoglobin and myoglobin illustrate both protein structure-function relationships and the molecular basis of genetic diseases such as sickle cell disease and the thalassemias. |
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| (HbS) is caused by a mutation that replaces glutamic acid at residue 6 in β-globin with valine (β6 Glu → Val). This amino acid substitution leads to the formation of linear polymers of deoxygenated HbS. Removal of O2 from HbS in the tissues exposes a complementary site that is also on the surface. The valine residue on the surface of HbS binds to the complementary site, linking the two tetramers together. As more tetramers become linked, linear polymers are formed that convert the normally flexible red cells into stiff, sickle-shaped cells. The inelastic, sickle-shaped cells plug the capillary beds and precipitate the sickling crisis. Note that the complementary site is not exposed in oxygenated blood, so the sickling is initiated in the peripheral tissues and joints. HbS is the most common hemoglobin variant worldwide, since the heterozygous form confers a resistance to malaria. It occurs primarily in the black population of the United States, affecting 1 in 500 newborns. When the mutation occurs on both chromosomes (chromosome 11), it produces sickle-cell disease; this has the most severe symptoms, since the RBC has no source of normal β-globin. With a mutation only on one chromosome (in heterozygotes), it produces sickle-cell trait (1 in 10 newborns); the production of nearly equal amounts of normal β-globin and βs-globin reduces the severity of the symptoms by lowering the degree of sickling that occurs. |
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| is caused by a mutation at the same site (position 6) as sickle cell hemoglobin except the alteration is glutamate to lysine (β6 Glu → Lys). Since lysine has little or no tendency to bind the complementary site, no sickling occurs. |
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| is caused by a tyrosine substitution (β58 His → Tyr) close to the heme iron; this stabilizes the heme iron in the oxidized form, preventing the binding of O2. Hb Boston is one of several hereditary methemoglobinemias that are characterized by cyanosis. |
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| is caused by a leucine substitution (α92 Arg → Leu) that weakens the salt bridges, causing them to break more easily. The resulting increase in O2 affinity, resulting from decreased sensitivity to negative allosteric effectors, makes it more difficult for RBCs to unload O2 in the tissues, creating hypoxia. This signals an increase in RBC production and leads to polycythemia. |
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| is caused by a methionine substitution (β98 Val → Met) that produces an unstable β-globin. The denaturation of the hemoglobin eventually leads to RBC fragility and hemolytic anemia. |
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| result from altered rates of globin synthesis. Unbalanced production of either -globin or β-globin leads to a class of diseases called thalassemias. These are primarily hemolytic anemias due to the production of altered tetramers |
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• Complete deletion of globin genes.
• Impaired RNA synthesis.
• Impaired primary mRNA splicing.
• Frameshift or nonsense mutations producing quickly degraded globins. |
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| The β-thalassemias include thalassemia major (two mutated β-globin genes; chromosome 11) and thalassemia minor (heterozygote). Thalassemia major is lethal by adulthood, whereas thalassemia minor produces only a mild anemia. The -thalassemias are more complicated, since the -globin is present before and after birth and there are two copies of the -globin gene on chromosome 16. The progressive loss of -globin genes results in more severe anemias, which affect the fetus. |
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