8885dc02_47-747/25/0310:05 AM Page54mac76mac76:385 Part I Structure and Catalysis Ordered water other Random variations in the positions of the electrons interacting with around one nucleus may create a transient electric di pole, which induces a transient, opposite electric dipole in the nearby atom. The two dipoles weakly attract each other, bringing the two nuclei closer. These weak at- tractions are called van der waals interactions. As Substrate the two nuclei draw closer together, their electron clouds begin to repel each other. At the point where the van der Waals attraction exactly balances this repulsive force. the nuclei are said to be in van der waals contact Each atom has a characteristic van der waals radius a measure of how close that atom will allow another to approach (Table 2-4). In the"space-filling"molecular models shown throughout this book, the atoms are de- picted in sizes proportional to their van der Waals radii. Weak Interactions Are crucial to macromolecular Structure and function The noncovalent interactions we have described (hy drogen bonds and ionic, hydrophobic, and van der Waals interactions)(Table 2-5) are much weaker than cova- Disordered water lent bonds. An input of about 350 kJ of energy is re- quired to break a mole of (6 X 102)C-C single bonds enzyme-substrate interaction nd about 410 k to break a mole of c-h bonds but little as 4 k is sufficient to disrupt a mole of typical van der Waals interactions. Hydrophobic interactions are also much weaker than covalent bonds, althoug they are substantially strengthened by a highly polar sol- vent (a concentrated salt solution, for example). Ionic interactions and hydrogen bonds are variable in strength, depending on the polarity of the solvent and stabilized gen-bonding ionic and obic interactions TABLE 2-4 van der Waals Radii and Covalent FIGURE 2-8 Release of ordered water favors formation of ar (Single-Bond)Radii of Some Elements enzyme-substrate complex. While separate, both enzyme and sub- Covalent radius for strate force neighboring water molecules into an ordered shell. Bind- Element radius(nm) single bond (nm) ing of substrate to enzyme releases some of the ordered water, and the resulting increase in entropy provides a thermodynamic push to- H 0.11 0.030 ward formation of the enzyme-substrate complex N 0.15 0.070 0.18 P 0.19 0.110 of the driving force for binding of a polar substrate (re 0.133 actant) to the complementary polar surface of an en- zyme is the entropy increase as the enzyme displaces ordered water from the substrate(Fig. 2-8) Sources: For van der Waals radii, Chauvin, R.( 1992)Explicit periodic trend of van der Waals radil. J Phys. Chem. 96, 9194-9197 For covalent radi, Pauling, L(1960)Nature of van der waals Interactions Are weak lote: van der waals radii describe the space filling dimensions of atoms. when two atoms Interatomic Attractions re joined covalently, the atomic radii at the point of bonding are less than the van der Waals radii, because the joined atoms are pulled together by the shared electron pair. The When two uncharged atoms are brought very close to- an der Waals interaction or a covalent bond is about equal he van der Waals or covalent radil, respectively, for the two atoms. Thus the gether, their surrounding electron clouds influence each length of a carbon-carbon single bond is about 0.077 nm +0.077 nm=0.154 nm
of the driving force for binding of a polar substrate (reactant) to the complementary polar surface of an enzyme is the entropy increase as the enzyme displaces ordered water from the substrate (Fig. 2–8). van der Waals Interactions Are Weak Interatomic Attractions When two uncharged atoms are brought very close together, their surrounding electron clouds influence each other. Random variations in the positions of the electrons around one nucleus may create a transient electric dipole, which induces a transient, opposite electric dipole in the nearby atom. The two dipoles weakly attract each other, bringing the two nuclei closer. These weak attractions are called van der Waals interactions. As the two nuclei draw closer together, their electron clouds begin to repel each other. At the point where the van der Waals attraction exactly balances this repulsive force, the nuclei are said to be in van der Waals contact. Each atom has a characteristic van der Waals radius, a measure of how close that atom will allow another to approach (Table 2–4). In the “space-filling” molecular models shown throughout this book, the atoms are depicted in sizes proportional to their van der Waals radii. Weak Interactions Are Crucial to Macromolecular Structure and Function The noncovalent interactions we have described (hydrogen bonds and ionic, hydrophobic, and van der Waals interactions) (Table 2–5) are much weaker than covalent bonds. An input of about 350 kJ of energy is required to break a mole of (6 1023) COC single bonds, and about 410 kJ to break a mole of COH bonds, but as little as 4 kJ is sufficient to disrupt a mole of typical van der Waals interactions. Hydrophobic interactions are also much weaker than covalent bonds, although they are substantially strengthened by a highly polar solvent (a concentrated salt solution, for example). Ionic interactions and hydrogen bonds are variable in strength, depending on the polarity of the solvent and 54 Part I Structure and Catalysis Substrate Enzyme Disordered water displaced by enzyme-substrate interaction Enzyme-substrate interaction stabilized by hydrogen-bonding, ionic, and hydrophobic interactions Ordered water interacting with substrate and enzyme FIGURE 2–8 Release of ordered water favors formation of an enzyme-substrate complex. While separate, both enzyme and substrate force neighboring water molecules into an ordered shell. Binding of substrate to enzyme releases some of the ordered water, and the resulting increase in entropy provides a thermodynamic push toward formation of the enzyme-substrate complex. Sources: For van der Waals radii, Chauvin, R. (1992) Explicit periodic trend of van der Waals radii. J. Phys. Chem. 96, 9194–9197. For covalent radii, Pauling, L. (1960) Nature of the Chemical Bond, 3rd edn, Cornell University Press, Ithaca, NY. Note: van der Waals radii describe the space-filling dimensions of atoms. When two atoms are joined covalently, the atomic radii at the point of bonding are less than the van der Waals radii, because the joined atoms are pulled together by the shared electron pair. The distance between nuclei in a van der Waals interaction or a covalent bond is about equal to the sum of the van der Waals or covalent radii, respectively, for the two atoms. Thus the length of a carbon-carbon single bond is about 0.077 nm 0.077 nm 0.154 nm. van der Waals Covalent radius for Element radius (nm) single bond (nm) H 0.11 0.030 O 0.15 0.066 N 0.15 0.070 C 0.17 0.077 S 0.18 0.104 P 0.19 0.110 I 0.21 0.133 van der Waals Radii and Covalent (Single-Bond) Radii of Some Elements TABLE 2–4 8885d_c02_47-74 7/25/03 10:05 AM Page 54 mac76 mac76:385_reb:
8885dc02_47-747/25/0310:05 AM Page55mac76mac76:385 Chapter 2 Water TABLE 2-5 Four Types of Noncovalent("Weak") through multiple weak interactions requires all these in fractions to be disrupted at the same time. because Interactions among Biomolecules in Aqueous Solvent the interactions fluctuate randomly, such simultaneous Hydrogen bonds disruptions are very unlikely. The molecular stability be- Between neutral groups stowed by 5 or 20 weak interactions is therefore much O11H-O- greater than would be expected intuitively from a sim- of small binding energie Between peptide bonds Macromolecules such as proteins, DNA, and RNA contain so many sites of potential hydrogen bonding or ionic, van der Waals, or hydrophobic interactions that lonic interactions the cumulative effect of the many small binding forces can be enormous. For macromolecules. the most stable Attraction (that is, the native) structure is usually that in which weak-bonding possibilities are maximized. The folding Repulsion of a single polypeptide or polynucleotide chain into its three-dimensional shape is determined by this princi- ple. The binding of an antigen to a specific antibody de- pends on the cumulative effects of many weak interac CH3 ch tions. As noted earlier, the energy released when an Hydrophobic interactions enzyme binds noncovalently to its substrate is the main source of the enzymes catalytic power. The binding of a hormone or a neurotransmitter to its cellular recep- tor protein is the result of weak interactions. One con sequence of the large size of enzymes and receptors is that their extensive surfaces provide many opportuni van der Waals interactions Any two atoms in ties for weak interactions. At the molecular level. the complementarity between interacting biomolecules re- flects the complementarity and weak interactions be tween polar, charged, and hydrophobic groups on the surfaces of the molecules When the structure of a protein such as hemoglobin the alignment of the hydrogen-bonded atoms, but they(Fig. 2-9) is determined by x-ray crystallography(see are always significantly weaker than covalent bonds. In aqueous solvent at 25C, the available thermal energy can be of the same order of magnitude as the strength of these weak interactions, and the interaction between olute and solvent (water) molecules is nearly as favor- able as solute-solute interactions. Consequently, hydro- gen bonds and ionic, hydrophobic, and van der waals interactions are continually formed and broken. Although these four types of interactions are indi- vidually weak relative to covalent bonds, the cumulative effect of many such interactions can be very significant For example, the noncovalent binding of an enzyme to its substrate may involve several hydrogen bonds and one or more ionic interactions, as well as hydrophobic and van der waals interactions The formation of each of these weak bonds contributes to a net decrease in the free energy of the system. We can calculate the sta (a)es bility of a noncovalent interaction, such as that of a small FIGURE 2-9 Water binding in hemoglobin. The crystal structure of molecule hydrogen-bonded to its macromolecular part. moglobin, shown(a) with bound water molecules(red spheres)and ner, from the binding energy Stability, as measured by b)without the water molecules. These water molecules are so firmly the equilibrium constant(see below) of the binding re- bound to the protein that they affect the x-ray diffraction pattern as action, varies exponentially with binding energy. The though they were fixed parts of the crystal. The gray structures with dissociation of two biomolecules(such as an enzyme red and orange atoms are the four hemes of hemoglobin, discussed and its bound substrate) associated noncovalently in detail in Chapter 5
the alignment of the hydrogen-bonded atoms, but they are always significantly weaker than covalent bonds. In aqueous solvent at 25 C, the available thermal energy can be of the same order of magnitude as the strength of these weak interactions, and the interaction between solute and solvent (water) molecules is nearly as favorable as solute-solute interactions. Consequently, hydrogen bonds and ionic, hydrophobic, and van der Waals interactions are continually formed and broken. Although these four types of interactions are individually weak relative to covalent bonds, the cumulative effect of many such interactions can be very significant. For example, the noncovalent binding of an enzyme to its substrate may involve several hydrogen bonds and one or more ionic interactions, as well as hydrophobic and van der Waals interactions. The formation of each of these weak bonds contributes to a net decrease in the free energy of the system. We can calculate the stability of a noncovalent interaction, such as that of a small molecule hydrogen-bonded to its macromolecular partner, from the binding energy. Stability, as measured by the equilibrium constant (see below) of the binding reaction, varies exponentially with binding energy. The dissociation of two biomolecules (such as an enzyme and its bound substrate) associated noncovalently through multiple weak interactions requires all these interactions to be disrupted at the same time. Because the interactions fluctuate randomly, such simultaneous disruptions are very unlikely. The molecular stability bestowed by 5 or 20 weak interactions is therefore much greater than would be expected intuitively from a simple summation of small binding energies. Macromolecules such as proteins, DNA, and RNA contain so many sites of potential hydrogen bonding or ionic, van der Waals, or hydrophobic interactions that the cumulative effect of the many small binding forces can be enormous. For macromolecules, the most stable (that is, the native) structure is usually that in which weak-bonding possibilities are maximized. The folding of a single polypeptide or polynucleotide chain into its three-dimensional shape is determined by this principle. The binding of an antigen to a specific antibody depends on the cumulative effects of many weak interactions. As noted earlier, the energy released when an enzyme binds noncovalently to its substrate is the main source of the enzyme’s catalytic power. The binding of a hormone or a neurotransmitter to its cellular receptor protein is the result of weak interactions. One consequence of the large size of enzymes and receptors is that their extensive surfaces provide many opportunities for weak interactions. At the molecular level, the complementarity between interacting biomolecules reflects the complementarity and weak interactions between polar, charged, and hydrophobic groups on the surfaces of the molecules. When the structure of a protein such as hemoglobin (Fig. 2–9) is determined by x-ray crystallography (see Chapter 2 Water 55 Hydrogen bonds Between neutral groups Between peptide bonds Ionic interactions Attraction Repulsion Hydrophobic interactions van der Waals interactions Any two atoms in close proximity Four Types of Noncovalent (“Weak”) Interactions among Biomolecules in Aqueous Solvent TABLE 2–5 G C D PO HOOO G C D G D PO HON B NH3 O O OOC NH3 H3N O O A O CH3 CH3 CH2 CH2 A A G CH D water (a) (b) FIGURE 2–9 Water binding in hemoglobin. The crystal structure of hemoglobin, shown (a) with bound water molecules (red spheres) and (b) without the water molecules. These water molecules are so firmly bound to the protein that they affect the x-ray diffraction pattern as though they were fixed parts of the crystal. The gray structures with red and orange atoms are the four hemes of hemoglobin, discussed in detail in Chapter 5. 8885d_c02_47-74 7/25/03 10:05 AM Page 55 mac76 mac76:385_reb: