Stability of native states A protein folded into its
native state or
native conformation typically has a lower
Gibbs free energy (a combination of
enthalpy and
entropy) than the unfolded conformation. A protein will tend towards low-energy conformations, which will determine the protein's fold in the
cellular environment. Because many similar conformations will have similar energies, protein structures are
dynamic, fluctuating between these similar structures.
Globular proteins have a core of
hydrophobic amino acid residues and a surface region of
water-exposed, charged,
hydrophilic residues. This arrangement may stabilize interactions within the tertiary structure. For example, in
secreted proteins, which are not bathed in
cytoplasm,
disulfide bonds between
cysteine residues help to maintain the tertiary structure. There is a commonality of stable tertiary structures seen in proteins of diverse function and diverse
evolution. For example, the
TIM barrel, named for the enzyme
triosephosphateisomerase, is a common tertiary structure as is the highly stable,
dimeric,
coiled coil structure. Hence, proteins may be classified by the structures they hold. Databases of proteins which use such a classification include
SCOP and
CATH. Folding
kinetics may trap a protein in a high-
energy conformation, i.e. a high-energy intermediate conformation blocks access to the lowest-energy conformation. The high-energy conformation may contribute to the function of the protein. For example, the
influenza hemagglutinin protein is a single polypeptide chain which when activated, is
proteolytically cleaved to form two polypeptide chains. The two chains are held in a high-energy conformation. When the local
pH drops, the protein undergoes an energetically favorable conformational rearrangement that enables it to penetrate the host
cell membrane. Some tertiary protein structures may exist in long-lived states that are not the expected most stable state. For example, many
serpins (serine protease inhibitors) show this
metastability. They undergo a
conformational change when a loop of the protein is cut by a
protease.
Chaperone proteins It is commonly assumed that the native state of a protein is also the most
thermodynamically stable and that a protein will reach its native state, given its
chemical kinetics, before it is
translated. Protein
chaperones within the cytoplasm of a cell assist a newly synthesised polypeptide to attain its native state. Some chaperone proteins are highly specific in their function, for example,
protein disulfide isomerase; others are general in their function and may assist most globular proteins, for example, the
prokaryotic GroEL/
GroES system of proteins and the
homologous eukaryotic heat shock proteins (the Hsp60/Hsp10 system).
Cytoplasmic environment Prediction of protein tertiary structure relies on knowing the protein's
primary structure and comparing the possible predicted tertiary structure with known tertiary structures in
protein data banks. This only takes into account the cytoplasmic environment present at the time of
protein synthesis to the extent that a similar cytoplasmic environment may also have influenced the structure of the proteins recorded in the protein data bank.
Ligand binding The structure of a protein, such as an
enzyme, may change upon binding of its natural ligands, for example a
cofactor. In this case, the structure of the protein bound to the ligand is known as holo structure, while the unbound protein has an apo structure. Structure stabilized by the formation of weak bonds between amino acid side chains - Determined by the folding of the polypeptide chain on itself (nonpolar residues are located inside the protein, while polar residues are mainly located outside) - Envelopment of the protein brings the protein closer and relates a-to located in distant regions of the sequence - Acquisition of the tertiary structure leads to the formation of pockets and sites suitable for the recognition and the binding of specific molecules (biospecificity). == Determination ==