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The Effects of Hydrogen Bonding on Physiology

Of the many great scientists of the 20th century Linus Pauling was greatly influential in elucidating
the principles of chemical bonding and applying those principles to biological molecules. In his 1939
book, The Nature of the Chemical Bond, Pauling describes the importance of hydrogen bonding in
biological molecules It has been recognized that hydrogen bonds restrain protein molecules to their
native configuration and I believe that as the methods of structural chemistry are further applied to
physiological problems it will be found that the significance of the hydrogen bond for physiology is
greater than that of any other single structural feature (Pauling 1939). As biochemistry has progressed
since the publication of Paulings book, it has become increasingly clear that Linus Paulings prediction
about hydrogen bonds was correct. Hydrogen bonds are largely responsible for the formation of protein
secondary structure. Changes to the ability of a protein to hydrogen bond correctly can cause major
changes in the structure and function of a protein, which will undoubtedly result in physiological
changes due to the altered nature of the protein.
The secondary structure of a polypeptide is largely determined by the propensity of amino acids in a
polypeptide chain to form hydrogen bonds. The arrangement of hydrogen bonds in polypeptides is
determined by factors such as bond angles and the amino acid residues that make up the chain. The
polypeptide backbone is made up of three major bonds, the N-C bond, the C-C bond, and the C-N bond
(Figure 1a). Due to the partial double bond character of the N-C bond (Figure 1b) only the C-C and C-N
bonds can be rotated (Nelson et al. 2008); the angles of these bonds are designated by the symbols
and respectively. The value of the and bond angles can, in principle, be any number between -180
and 180 degrees; however, steric interference from the backbone and from certain amino acid residues
will often restrict the bonds to certain angles (Nelson et al. 2008). The ability of the C-C and the C-N
bonds to rotate results in different secondary structures which are stabilized by the formation of
hydrogen bonds between the hydrogen of the amine group and the oxygen of the carbonyl group. A
very common secondary structure for many proteins is the -helix. The -helix is a polypeptide chain
which has bond angles of -57 for and -47 for ; this results in a right-handed single helix structure
(Figure 2a). The hydrogen bonding in an -helix occurs between the amine and carbonyl groups of the
same polypeptide. Another common secondary protein structure is the -sheet. In the -sheet several
polypeptides hydrogen bond with each other to form continuous zigzag structures; -sheets can form
parallel (=-119, =+113) or antiparallel (=-139, =+135) to each other (Figure 2b).
The formation of -helices, -sheets, or any other secondary structure will also rely on the types of
amino acid residues that reside in the polypeptide chain. Certain amino acids placed in the middle of the
polypeptide chain will interfere with the ability of the polypeptide to hydrogen bond, resulting in
restrictions to the secondary structure (Nelson et al. 2008). For example, the structure of proline, where
the side chain is covalently bonded to the Nitrogen of the polypeptide backbone (Figure 3) does not
allow for hydrogen bonding and, as a result; polypeptides with proline in the middle of the structure will
not form stable -helices (Kim et al. 1999). Certain amino acids placed at the end of polypeptides will
also destabilize certain structures. The hydrogen bonding that occurs in an -helix structure results in a
net dipole across the structure; Because amino acids at the C and N terminus do not participate fully in
the hydrogen bonding the C-terminus caries a slight negative charge and the N-terminus carries a slight
negative charge. In order to stabilize these charges, amino acids with positive side chains are normally
associated with the C-terminus while amino acids with negative side chains are associated with the N-
terminus. Should one terminus accumulate too much charge the entire -helix becomes destabilized
(Nelson et al. 2008). The formation of -sheets is largely dependent on the size of the amino acid
residues present in the structure. Large amino acid R-groups will interact with each other in a -sheet
while smaller groups will not. As a result, most -sheet structures will have a large percentage of small
amino acid residues in the sequence; this is the case with -keratins, which contain large proportions of
glycine and alanine residues, the smallest amino acids (Nelson et al. 2008).
The ability of a polypeptide to form its correct secondary structure is highly important to its
function. Should a mutation occur in the genetic code that causes a single change in the amino acid
sequence then the polypeptide may not form the correct secondary structure, affecting the final protein
product. Three major examples of this are

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