Molecular Simulation and Systems Biology - Systems Biology: Networks, Models, and Applications - page 77

visited by the system during the simulation. Such energy surfaces
are characterized as rough , and they present formidable challenges in
the field of simulation. Rough energy landscapes result in the occur-
rence of rare events— the infrequent crossings of high free energy
regions — that are difficult to characterize.
EXAMPLES OF MOLECULAR SIMULATION APPLIED TO BIOLOGICAL
SYSTEMS
Some Scientific Questions Addressed by Molecular Simulation
How does protein folding happen? Many proteins fold reversibly
into unique shapes. What this means is, first, that there is a unique
three-dimensional shape for the protein in the sense that most or all
copies of it in an ensemble adopt the same shape. Second, if condi-
tions are altered, for example, by heating or by adding salts of
different types, or by adding acid or base so as to change the pH, the
protein will unfold into a denatured state, where its functional prop-
erties are lost. Reversibility means that when the conditions are
restored, the protein will refold and its function will be restored. The
reason this is so remarkable is that even very small proteins can adopt
a very large number of conformations that are locally stable, and
yet reversibly folding proteins always refold to one of a very small set
of the most stable conformations! The hypothesis is that there is a
driving force for folding that is actually coded into the amino acid
sequence; this force helps to guide the protein into the right shape.
A great deal of research is underway to understand exactly how this
happens.
Is there a pathway to protein folding? Are there well-defined structural
intermediates and traps observed during protein folding? A key question
for those involved in the field of protein folding relates to the pathway
or mechanism of folding. Many view protein folding as the progression
of the protein from one structure to another until the final folded struc-
ture develops. In this view, the mechanism of folding is a specification
of the intermediate structures. Of course, there may not be only one,
but rather many pathways possible, all of which have different likeli-
hoods of occurring. At the other end of the spectrum of possibilities,
there may be an infinite number of pathways, such that any arbitrary
unfolded structure takes its own path to the folded state. The answer
to this question of the number and nature of the folding pathways
will probably be different for different proteins. Simulations can shed
light on these aspects of the nature of protein folding. A view of the
kinetics of folding needs to acknowledge the fact that in general
there are multiple pathways each with different likelihoods of occur-
rence as well as different times over which folding will be observed.