Biomedical Engineering Reference
In-Depth Information
1.1.1
Structure of Macromolecular Systems
Although structure determination is an essential part of the study of all macro-
molecules, we will mainly be concerned with proteins in this chapter, so we briefly
describe the basic, hierarchical rules of protein structural organization. A protein
is made of only a few atom types, principally H, C, N, O and S. These atoms are
chemically bonded in different ways to form 20 distinct types of amino acids, each
made of about 10-20 atoms. The amino acids are themselves chemically linked (via
a peptide bond) in a topologically linear polypeptide chain: the sequence of amino
acids in this chain is called the
primary
structure of the protein. In the present
chapter we will not be concerned with either the forming or the breaking of such
covalent bonds, which involves energy changes well beyond those involved in the
formation of the majority of protein complexes.
Although the primary structure of a protein is often constant, the chain itself has
many degrees of freedom, allowing atoms in different regions to interact via weaker,
non-covalent
forces. Such influences include van der Waals interactions, hydrogen
bonding, the hydrophobic effect, etc. They tend to produce local folding of the
chain, in particular
secondary
structural elements, of which examples are regularly
repeating structures such as alpha helices or beta hairpins. At a higher level, the
different secondary structural elements and remaining chain regions fold up still
further into a globular domain, which is stabilized by so-called
tertiary
interactions.
If a given protein involves multiple domains, their precise structural interaction is
described by the
quaternary
structure. An essential fact for most proteins is that the
polypeptide chain is thus folded into a particular, highly ordered three-dimensional
shape, which is what we usually will refer to as the structure of the protein.
1
Structural information obtained for macromolecular systems has proven essen-
tial in interpreting physical, biochemical, and functional data. An elite club of
experimental techniques, dominated by X-ray crystallography and NMR, plays
an enormous role in biological and pharmaceutical research by providing three-
dimensional structures of macromolecules—that is, the
x, y
and
z
coordinates of
each of the thousands of atoms in the molecule. This information is stored in
a public repository, the Protein Databank (PDB,
http://www.rcsb.org/pdb
)[
58
].
Determination of the structures of individual proteins is now commonplace: the
PDB currently contains over 75,000 entries, with hundreds added each month.
Two main experimental techniques are being used to solve the structures of
macromolecular systems and populate the PDB. The first, X-ray crystallography,
gained importance after Kendrew and Perutz used it to solve the structures of myo-
globin and hemoglobin, a key achievement for which they were awarded the Nobel
prize in chemistry in 1962. X-ray crystallography has proved to be particularly
well adapted to biological structure determination, as it allows one to obtain atomic
1
While single-chain proteins are common, one protein may include more than one polypeptide
chain. Multiple chains are frequently covalently bonded via a disulfide bond formed between
cysteine residues.
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