Computer models were used to examine whether and under what conditions the multimeric protein complex is inhibited by high concentrations of one of its components-an effect analogous to the prozone phenomenon in precipitin tests. A series of idealized simple ''ball-and-stick'' structures representing small oligomeric complexes of protein molecules formed by reversible binding reactions were analyzed to determine the binding steps leading to each structure. The equilibrium state of each system was then determined over a range of starting concentrations and K d s and the steady-state concentration of structurally complete oligomer calculated for each situation. A strong inhibitory effect at high concentrations was shown by any protein molecule forming a bridge between two or more separable parts of the complex. By contrast, proteins linked to the outside of the complex by a single bond showed no inhibition whatsoever at any concentration. Nonbridging, multivalent proteins in the body of the complex could show an inhibitory effect or not depending on the structure of the complex and the strength of its bonds. On the basis of this study, we suggest that the prozone phenomenon will occur widely in living cells and that it could be a crucial factor in the regulation of protein complex formation.In the precipitin reaction widely used by immunologists, increasing amounts of soluble antigen are added to a series of tubes each containing a fixed amount of antibody-containing serum. As the antigen increases, the quantity of precipitate also increases up to a maximum and then declines. The basis for this phenomenon, for which the term ''prozone'' was originally used (1, 2), is well understood and depends on the fact that the precipitates are made from a three-dimensional lattice of antigen and antibody molecules (3). Macroscopic precipitates form only when antibody and antigen are in optimal proportions, and if either molecule is present in excess, small soluble complexes are produced instead. With excess antigen, for example, the soluble complexes consist of antibody molecules surrounded by multiple molecules of antigen.There is reason to think that a similar effect may occur in the formation of multimeric protein complexes in living cells. Many if not most protein molecules in a living cell are part of multiprotein assemblies held together by noncovalent bonds, such as multimeric enzymes and receptor complexes (4-8). Such complexes have a definite structure and composition, and their formation depends in part on a series of diffusion-limited binding reactions influenced by the concentrations of participating protein molecules and their binding affinities for each other. Thus, if one species is present at much higher levels than the others, we might anticipate that something similar to the prozone phenomenon could operate. That is, we might find that formation of the structurally complete complex would be suppressed at the expense of smaller, incomplete clusters of proteins. Because the function of most protein com...
We have trained a computer model of a simple cell-signaling pathway to give specified responses to a pulse of an extracellular ligand. The pathway consists of two initially identical membrane receptors, each of which relays the concentration of the ligand to the level of phosphorylation of an intracellular molecule. Application of random "mutational" changes to the rate constants of the pathway, followed by selection in favor of certain outputs, generates a variety of wave forms and dose-response curves. The phenotypic effect of mutations and the frequency of selection both affect the efficiency with which the pathway achieves its target. When the pathway is trained to give a maximal response at a specific concentration of the stimulating ligand, it gives a consistent pattern of changes in which the two receptors diverge, producing a high-affinity form with excitatory output and a low-affinity form with inhibitory output. We suggest that some high- and low-affinity forms of receptors found in present-day cells might have originated by a similar process.
Safety is a fundamental requirement in any human-robot collaboration scenario. To ensure the safety of users for such scenarios, we propose a novel Virtual Barrier system facilitated by an augmented reality interface. Our system provides two kinds of Virtual Barriers to ensure safety: 1) a Virtual Person Barrier which encapsulates and follows the user to protect them from colliding with the robot, and 2) Virtual Obstacle Barriers which users can spawn to protect objects or regions that the robot should not enter. To enable effective human-robot collaboration, our system includes an intuitive robot programming interface utilizing speech commands and hand gestures, and features the capability of automatic path re-planning when potential collisions are detected as a result of a barrier intersecting the robot's planned path. We compared our novel system with a standard 2D display interface through a user study, where participants performed a task mimicking an industrial manufacturing procedure. Results show that our system increases the user's sense of safety and task efficiency, and makes the interaction more intuitive.
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