[A] Locomotion of a cell is enabled by a reversible rotary propeller of the bacterial flagellum [119]. [B] Nucleocytoplasmic transport of macromolecules occurs in a regulated fashion through the nuclear pore complex [120•]. [C] A number of cellular functions, including muscle contraction, cell motility, cell division and cytokinesis, depend on the assembly and maintenance of branched actin filaments (http://www.cgl.ucsf.edu/chimera/ImageGallery/). [D] The folding of many proteins is catalyzed inside the chaperonin cavity [7] (http://www.cgl.ucsf.edu/chimera/ImageGallery/). [E] The HIV-1 core assembles inside the maturing virion [121]. [F] Synthesis of ATP in mitochondria and chloroplasts is catalyzed by ATP synthase (http://www.mrc-dunn.cam.ac.uk/research/atp_synthase).

[A] Several important terms used in the text are illustrated by a process of four key states (circled solid shapes) connected by transitions (arrows). [B] Illustration of conformational heterogeneity. [C] Illustration of kinetic heterogeneity, showing several paths through the graph. Definitions of the terms can be found in Table 1.

The x-axis represents the size of the systems that can be explored by each method in nanometers. The y-axis represents the time scales that can be reached. The methods and abbreviations are described in Table 2.

The degradation process is part of a larger pathway, consisting of activation of ubiquitin, conjugation of the protein substrate and ubiquitins, degradation of the tagged protein, and deubiquitination to recycle the ubiquitins (bottom). The degradation process (top) is modeled by four key states and transitions between them, discussed in more detail in the text. The modeled system involves the 26S proteasome, the E3 ligase enzyme and the ubiquinated substrate protein. The four key states of the model are: [A] stable holo 26S, [B] recruitment of polyubiquinated substrate, [C] storage of substrate inside the proteasome and [D] disassociated and disassembled regulator particle. Arrows show transitions between states. As more information is obtained, the model can become more detailed by adding key states, increasing the spatial resolution of each key state, and mapping trajectories between key states.