Page 165 - Academic Press Encyclopedia of Physical Science and Technology 3rd BioChemistry

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Encyclopedia of Physical Science and Technology EN013D-616 July 27, 2001 12:5

Protein Structure 205

without reducing the thermal stability of the folded protein portional to the sixth power of the separation. Although
are quite limited. Studies on T4 lyszoyme have shown that these forces are very weak there are an enormous num-
if suitable locations can be found, the degree of stability ber present within a folded protein such that they to con-
introduced into a protein is proportional to the size of the tribute significantly stability of the folded state. As a
closed loop generated by forming a disulfide bond. group, the Van der Waals forces are important for sta-
bilizing interactions between proteins and their comple-
mentary ligands whether the ligands are proteins or small
D. Ionic Interactions
molecules.
The association of two oppositely charged ionic groups
in a protein is known as a salt bridge or ion pair and is a VII. TERTIARY STRUCTURE
common feature of most proteins. Typically these inter-
actions contribute very little to protein stability since the
A. Protein Folding Rules
isolated ionic groups are so effectively solvated by water.
As a consequence very few unsolvated salt bridges are Examination of a large number of protein structures has
found in the interior of proteins. Furthermore, salt bridges yielded a few common rules about the folds that proteins
are rarely conserved in orthologous proteins. can adopt as listed in the following. The theoretical basis
for these features is not well understood, but most appear
to result from the chirality of the amino acids, entropic
E. Dipole–Dipole Interactions
considerations, and the necessity to establish a hydropho-
Dipole–dipole interactions are weak interactions that bic core.
arise from the close association of permanent or in-
duced dipoles. Collectively these forces are known as 1. Secondary structural elements that are close in the
Van der Waals interactions. Proteins contain a large num- sequence of a protein are often adjacent in the folded
ber of these interactions, which vary considerably in protein. It is less common to find secondary structural
strength. elements that are far apart in the sequence and close
The strongest interactions are observed between perma- together in the structure. The exception to this arises
nent dipoles and are an important feature of the peptide where an auxiliary domain has clearly been inserted
bond. In the peptide bond the dipoles associated with the into a loop in a protein. This is probably the most
peptide carbonyl and amide group are aligned and give entropically favorable way to arrange secondary
rise to a significant dipole moment (3.5 Debye units for structural elements within a folded protein.
a peptide bond versus 1.85 for a water molecule). These 2. Adjacent parallel β-strands are almost exclusively
interactions fall off with the inverse of the second to third connected by right-handed crossovers (Fig. 9). It is
power when the dipoles are fixed and to the sixth power believed that this feature arises from the chirality of
when they are free to rotate. So, for example, there is a the amino acids that leads to a net right-handed twist
substantial positive dipole at the amino-terminal end of in the polypeptide chain.
an α-helix where the dipoles are constrained and aligned. 3. There are no topological knots in proteins.
As a consequence the N-terminal end of an α-helix is of- 4. Proteins always contain more than one layer of
ten utilized to bind negatively charged ligands in enzyme secondary structural elements. This rule arises
active sites. because proteins always contain a hydrophobic core
Permanent dipoles may also induce a dipole moment in formed by the association of hydrophobic side chains.
a neighboring atom or group. This is a stabilizing interac- 5. α-Helices and β-sheets typically associate in discrete
tion, but is much weaker than that observed between per- layers of the same type of secondary structural
manent dipoles. These type of interactions are important elements. This feature is the consequence of the
since they change the charge distribution of neighboring necessity to fulfill the hydrogen bonding
atoms which in turn can profoundly influence activation requirements of the polypeptide chain and packing
barriers in enzyme catalyzed reactions. considerations. Typically the interior of a protein does
London or dispersion forces are the weakest of all not contain any holes larger than a water molecule.
of the dipole–dipole. These are best described in quan- Because α-helices and β-strands differ greatly in their
tum mechanical terms, but may be viewed qualitatively cross-sectional diameters, inclusion of these in the
as the consequence of the transient asymmetry in the same layer would result in a poorly packed protein
charge distribution in a neutral atom that induces a fa- interior. In addition a mixture of α-helices and
vorable dipole in a neighboring neutral atom thus lead- β-strands in the same layer would not fulfill the
ing to a weak attraction. These forces are inversely pro- hydrogen bonding potential of the β-strand.