Whereas previously we have successfully utilized the
folding funnels concept to rationalize binding mechanisms
(Ma B, Kumar S, Tsai CJ, Nussinov R, 1999, Protein
Eng 12:713–720) and to describe binding (Tsai
CJ, Kumar S, Ma B, Nussinov R, 1999, Protein Sci
8:1181–1190), here we further extend the
concept of folding funnels, illustrating its utility
in explaining enzyme pathways, multimolecular associations,
and allostery. This extension is based on the recognition
that funnels are not stationary; rather, they are
dynamic, depending on the physical or binding
conditions (Tsai CJ, Ma B, Nussinov R, 1999, Proc
Natl Acad Sci USA 96:9970–9972). Different
binding states change the surrounding environment of proteins.
The changed environment is in turn expressed in shifted
energy landscapes, with different shapes and distributions
of populations of conformers. Hence, the function of a
protein and its properties are not only decided by the
static folded three-dimensional structure; they are determined
by the distribution of its conformational substates, and
in particular, by the redistributions of the populations
under different environments. That is, protein function
derives from its dynamic energy landscape, caused by changes
in its surroundings.