482
10 The Statistical Basis of Bioenergetics
N–H groups tilted downward to the terminus with the C=O tilted upward. The side
chains are on the outside of the helix, slightly tilted downward. There are typically
about three or four turns of an alpha coil before an alteration of chain angles.
The beta ‘pleated sheets’ 50 are also formed by hydrogen bonds, but this time
perpendicular to segments of the protein backbone which lie next to each other,
with the direction of the chain segments either parallel or anti-parallel. The sidechains point alternately up and down perpendicular to the sheet, with the distance
between every second chain about 7 Å.
In turn, the proteins with coil and sheet segments fold into globular tertiary
structures. Loop segments of the protein chain (called β turns) form in between
the coils and sheets.
The tertiary structure is determined by van der Waals forces, hydrogen bonds,
dipole forces, Coulombic interactions of charged side-chains and ions, and sometimes by cross-linking chemical bonds, such as a disulfide bond. Particularly
important for the secondary to tertiary transformation of proteins are the side-chain
interactions due to water affinity (hydrophobic or hydrophilic).
Quaternary structures are formed when several proteins are held together, such
as hemoglobin, which has four subunits, two of alpha and two of beta structures.
DNA polymerase has ten subunits.
In thermodynamic terms, the folding process releases energy of binding (but
less than 0.43 eV/Da), and also causes a drop in entropy as the protein becomes
more ordered. As in all chemical processes at constant temperature and pressure,
the Gibbs free energy, G = E + pV − T S = H − T S, must drop in value if
the reaction is to go forward. Since G = H − T TS, the heat released is the
drop in the enthalpy. This means −H per degree, must exceed the entropy drop
−S, i.e. the energy releases across the protein chain per unit temperature as the
chain folds cannot be less than the value of |S| representing the order produced.
As folding occurs in a water solution, hydrophobic regions are likely to be forced
inside the protein tertiary structure. The solution pH and various salts also can affect
the dynamics of chain folding. In addition, for complex proteins, there are so-called
chaperone proteins that stabilize various configurations of the folding protein until
the folding of a given region is complete. Also, there are catalysts that can speed the
process and facilitate disulfide bonds, when they are required.
However, beginning with the work of Christian Anfinsen, 51 we know that
proteins can fold into their natural configurations without the help of chaperones
or catalysts, although time scales will lengthen. Most small proteins (less than 100
amino acids) can even be denatured and re-natured by raising and lowering the
temperature. Thus, the final configuration is determined by valleys in an energy
landscape taken as a function of the multidimensional space of the two angles of
50 The beta sheet structure was first properly described by Linus Pauling and Robert Cory in 1951.
51 C.B. Anfinsen, E. Haber, M. Sela, F.H. White, Kinetics of formation of native ribonuclease
during oxidation of reduced polypeptide chain. PNAS 47, 1309–1314 (1961).
10 The Statistical Basis of Bioenergetics
N–H groups tilted downward to the terminus with the C=O tilted upward. The side
chains are on the outside of the helix, slightly tilted downward. There are typically
about three or four turns of an alpha coil before an alteration of chain angles.
The beta ‘pleated sheets’ 50 are also formed by hydrogen bonds, but this time
perpendicular to segments of the protein backbone which lie next to each other,
with the direction of the chain segments either parallel or anti-parallel. The sidechains point alternately up and down perpendicular to the sheet, with the distance
between every second chain about 7 Å.
In turn, the proteins with coil and sheet segments fold into globular tertiary
structures. Loop segments of the protein chain (called β turns) form in between
the coils and sheets.
The tertiary structure is determined by van der Waals forces, hydrogen bonds,
dipole forces, Coulombic interactions of charged side-chains and ions, and sometimes by cross-linking chemical bonds, such as a disulfide bond. Particularly
important for the secondary to tertiary transformation of proteins are the side-chain
interactions due to water affinity (hydrophobic or hydrophilic).
Quaternary structures are formed when several proteins are held together, such
as hemoglobin, which has four subunits, two of alpha and two of beta structures.
DNA polymerase has ten subunits.
In thermodynamic terms, the folding process releases energy of binding (but
less than 0.43 eV/Da), and also causes a drop in entropy as the protein becomes
more ordered. As in all chemical processes at constant temperature and pressure,
the Gibbs free energy, G = E + pV − T S = H − T S, must drop in value if
the reaction is to go forward. Since G = H − T TS, the heat released is the
drop in the enthalpy. This means −H per degree, must exceed the entropy drop
−S, i.e. the energy releases across the protein chain per unit temperature as the
chain folds cannot be less than the value of |S| representing the order produced.
As folding occurs in a water solution, hydrophobic regions are likely to be forced
inside the protein tertiary structure. The solution pH and various salts also can affect
the dynamics of chain folding. In addition, for complex proteins, there are so-called
chaperone proteins that stabilize various configurations of the folding protein until
the folding of a given region is complete. Also, there are catalysts that can speed the
process and facilitate disulfide bonds, when they are required.
However, beginning with the work of Christian Anfinsen, 51 we know that
proteins can fold into their natural configurations without the help of chaperones
or catalysts, although time scales will lengthen. Most small proteins (less than 100
amino acids) can even be denatured and re-natured by raising and lowering the
temperature. Thus, the final configuration is determined by valleys in an energy
landscape taken as a function of the multidimensional space of the two angles of
50 The beta sheet structure was first properly described by Linus Pauling and Robert Cory in 1951.
51 C.B. Anfinsen, E. Haber, M. Sela, F.H. White, Kinetics of formation of native ribonuclease
during oxidation of reduced polypeptide chain. PNAS 47, 1309–1314 (1961).