The concept of protein conformational landscape. A) Any protein structure exists in solution as a population of interconverting conformers, shown here as minima on the free energy curve, which represents a one-dimensional cross-section through the high-dimensional energy surface of a protein. In the example given, a population of conformers is composed of three families (A, B, and C). Families are composed of groups of related conformers, while groups, in turn, are composed of yet smaller divisions (not shown). The rates of interconversions are defined by the energy barriers separating alternative conformations. 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. B) Changes in external (environmental) conditions (pH, temperature, pressure, ionic strength, etc.) or in the internal state of the protein (e.g. ligand binding, mutation, posttranslational modification) often lead to redistribution of protein conformers and altered rates of their interconversions, i.e. to a reshaping of protein conformational landscape.