Molecular Simulation and Systems Biology - Systems Biology: Networks, Models, and Applications - page 78

Figure 3.5 The relative concentration versus time of various conformations of
an ensemble of peptides. The starting ensemble consisted entirely of fully
extended conformations.
(See figure 3.5, which shows the relative populations of various types
of protein conformations observed as a function of time for the folding
of a small hairpin-shaped peptide, the hairpin motif from protein G.)
How is protein structure affected by temperature? Another issue of
concern to people who study protein folding relates to the thermody-
namic stability of proteins. As a collection of proteins is heated, they
will unfold, but each member of the collection may adopt a different
unfolding path. An important aspect of thermally induced folding
and unfolding is the determination of the relative concentrations of
various intermediate structures that are observed at each temperature.
A tabulation of these structures can give some insight into the ways
proteins might misfold, which, in turn, can be related to the effect a
genetic mutation can have on protein stability and misfolding (figure 3.6).
What is the effect of mutations on both thermodynamics and kinetics?
These questions are of more than academic interest. Genes contain the
instructions for building proteins from amino acids. Genetic mutations
usually cause disease because defective proteins are manufactured.
There are many genetic diseases that have become known as conforma-
tional diseases [22]. These are diseases associated with mutations that
cause proteins to misfold or to fold so slowly that they are unable
to perform their function before being degraded by natural protein
cleanup processes that exist in the cell. In light of this, a very important
area that can be studied by simulation is how various types of mutation