Cooperativity, molecular basis

The molecular basis by which interferons promote their characteristic effects, in particular antiviral activity, is understood at least in part. Interferon stimulation of the JAK-STAT pathway induces synthesis of at least 30 different gene products, many of which cooperate to inhibit viral replication. These antiviral gene products are generally enzymes, the most important of which are 2 -5 oligoadenylate synthetase (2,5-A synthetase) and the eIF-2a protein kinase. 

All these observations prompt the question as to what the redox potentials are for the c and di hemes under equilibrium conditions. This issue is currently under study, and all that can be said here is that the enzyme does not give a straightforward redox titration. In particular, and in contrast to the observations made under pulse radiolysis conditions, the c and di hemes titrate together, suggesting a cooperativity of behavior between them (see note added in proof). It remains to elucidate the molecular basis for this effect. 

The molecular basis of site-site cooperativity in ATP synthase still remains unelucidated [46], and the absence of any direct evidence for cooperativity (despite almost three decades of effort) is explained, within the framework of the torsional mechanism, by the fact that site-site cooperativity does not exist in the physiological, steady state mode of functioning. Since, according to the torsional mechanism, no rotation takes place in uni-site or bi-site catalysis... 

Thus, specific interactions directly determine the spectroscopic features due to hydrogen bonding of the water molecules, while unspecific interactions arise in all or many polar liquids and are not directly related to the H-bonds. Now it became clear that the basis of four different processes (terms) used in Ref. [17] and mentioned above could rationally be explained on a molecular basis. One may say that specific interactions are more or less cooperative in their nature. They reveal some features of a solid state, while unspecific interactions could be understood in terms of a liquid state of matter, if we consider chaotic gas-like motions of a single polar molecule, namely, rotational motions of a dipole in a dense surroundings of other molecules. The modem aspect of the spectroscopic studies leads us to a conclusion that both gas-like and solid-state-like effects are the characteristic features of water. In this section we will first distinguish between the following two mechanisms of dielectric relaxation ... 

The molecular basis for the cooperativity effects in hemoglobins has been worked out in some detail. However, before delving into that, it is necessary to... 

Murphy KP, Bhakuni V, Xie D, Freire E (1992) Molecular basis of cooperativity in protein folding. III. Structural identification of cooperative folding units and folding intermediates, J Mol Biol, 227 293-306... 

There are essentially two types of control mechanisms for biochemical switching allosteric cooperative transition and reversible chemical modification. Allosteric cooperativity, which was discussed in Chapter 4, was discovered in 1965 by Jacques Monod, Jefferies Wyman, and Jean-Picrrc Changeux [143], and independently by Daniel Koshland, George Nemethy and David Filmer [116]. The molecular basis of this phenomenon, which is well understood in terms of three-dimensional protein crystal structures and protein-ligand interaction, is covered in every biochemistry textbook [147] as well as special treatises [215],... 

Although DSC and other physical techniques have made considerable contributions to the elucidation of the nature of lipid-protein interactions, several outstanding questions remain. For example, it remains to be dehnitively determined whether some integral, transmembrane proteins completely abolish the cooperative gel-to-liquid-crystalline phase transition of lipids with which they are in direct contact or whether only a partial abolition of this transition occurs, as is suggested by the studies of the interactions of the model transmembrane peptides with phospholipids bilayers (see above). The mechanism by which some integral, transmembrane proteins perturb the phase behavior of very large numbers of phospholipids also remains to be determined. Finally, the molecular basis of the complex and unusual behavior of proteins such as the concanavalin A receptor and the Acholeplasma laidlawii B ATPase is still obscure (see Reference 17). 

This chapter sets the tone for the entire book as it delineates the molecular basis of cooperativity, a crucial biomolecular concept largely overlooked in drug design. Cooperativity is shown to be tightly related to a particular molecular attribute of target proteins known as wrapping. This structure-based feature and its exploitation in the contexts of drug safety, specificity, and personalized therapy will become the leitmotiv of the book. 

Fernandez A, Zhang X, Chen J (2008) Folding and wrapping soluble proteins Exploring the molecular basis of cooperativity and aggregation. Prog Nucleic Acids Res Transl Sci 83 57-87... 

Hsp70 proteins with their co-chaperones and cooperating chaperones thus constitute a complex network of folding machines. This chapter describes the molecular basis of this network. Particular emphasis is given to the DnaK system of Escherichia coli as it is the best understood Hsp70 system, and to the mechanistic differences between Hsp70 family members. 

Most significantly, however, the molecular basis for positive cooperativity and the result of increased functional efficiency in designed elastic-contractile model proteins has been experimentally determined to be the competition for water that occurs between oil-like domains and charged groups constrained to coexist within a protein structure (see immediately below and Chapter 5, section 5.1.7.4). This represents the principal statement of the Mechanistic Assertion. 

---