The concept of the energy landscape. A) As a ball rolling down a rugged landscape under the force of gravity strives to minimize its potential energy, a folding protein structure descending a virtual energy landscape strives to minimize a thermodynamic potential called the Gibbs free energy. The "real" energy landscape of a protein is highly multidimensional; however, many qualitative properties of the protein folding process such as, for example, multiplicity of folding pathways and intermediate energy minima or "traps" in which a partially folded structure may become stuck on its way to the bottom of the landscape are conveniently captured and visualized in low-dimensional sections of the energy landscape, as shown here. (Reprinted with permission from Ken Dill, http://www.dillgroup.ucsf.edu/). B) The bottom of the energy landscape, which corresponds to a native (folded) structure, is a rugged landscape in itself, meaning that any native protein structure exists in solution as a population of interconverting conformational states that are separated by energy barriers of varying heights. The latter define the probabilities and thus rates of interconversions. Interconversions on timescales of microseconds and slower usually correspond to large-scale collective (domain) motions within the protein structure, which are relatively rare. Loop motions and side-chain rotations typically occur on timescales of pico- to microseconds, while atom fluctuations occur on timescales of picoseconds and faster.