Assembly reactions folded protein

Standard molecular mechanics (MM) force fields have been developed that provide a good description of protein structure and dynamics,21 but they cannot be used to model chemical reactions. Molecular dynamics simulations are very important in simulations of protein folding and unfolding,22 an area in which they complement experiments and aid in interpretation of experimental data.23 Molecular dynamics simulations are also important in drug design applications,24 and particularly in studies of protein conformational changes,25,26 simulations of the structure and function of ion channels and other membrane proteins,27-29 and in studies of biological macromolecular assemblies such as F-l-ATPase.30... 

We have attempted to integrate chemical concepts throughout the text. They include the mechanistic basis for the action of selected enzymes, the thermodynamic basis for the folding and assembly of proteins and other macromolecules, and the structures and chemical reactivity of the common cofactors. These fundamental topics underlie our understanding of all biological processes. Our goal is not to provide an encyclopedic examination of enzyme reaction mechanisms. 

Figure 26.17 Dynamical processes for molecular information and expression in the cases of protein (upper) and steroidal molecules (lower), (a) A molecule as an information carrier, (b) a molecular architecture based on folding or assembly, (c) a host-guest complexation, and (d) a guest exchange reaction.

In vivo, the correct assembly of proteins is guided by a family of cellular proteins termed molecular chaperones, e.g., heat shock protein (HSP), nuleoplasmins, and chaperonins. Chaperones bind to the intermediate that tends to aggregate, and either assembles the intermediate to the native state or renders the intermediate void of further reaction to form an aggregate. Normally, all proteins should fold without molecular chaperones. Proteins that tend to form aggregates, like those shown in the above mechanisms, bind to a chaperone to yield the native state. 

Another general feature of the protein folds that confers an important element of fitness is that they generally contain a relatively compact hydrophobic core. This provides a convenient reaction chamber for organic syntheses that are, for the most part, difficult to carry out unless water is excluded. The dense hydrophobic core may also confer on many folds the ability to stack together into various stable supramolecular assemblies that form the basic elements of the cytoskeleton nucleosomes, cytoplasmic filaments, microtubules, and so forth. 

The principal targets for facilitated folding by CCT in cooperation with prefoldin are the cytoskeletal proteins actin and tubulin. The actin monomer assembles into microfilaments, while the subunit that forms microtubules is the tubulin heterodimer, which consists of a single a- and a single /f-tubulin polypeptide. Though actin can be folded to the native state via one or more cycles of ATP-dependent interaction with CCT, this is not the case for either a- or /Ttubulin. Tubulin subunits released from CCT are assembled into a/fi heterodimers by interaction with several tubulin-specific chaperones known as cofactors in a reaction that depends on GTP hydrolysis by the cofactor-bound tubulin. 

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