The Importance of Electrostatics

In biochemical systems, acid-base and redox reactions are essential. Electron transfer plays an obvious, crucial role in photosynthesis, and redox reactions are central to the response to oxidative stress, and to the innate immune system and inflammatory response. Acid-base and proton transfer reactions are a part of most enzyme mechanisms, and are also closely linked to protein folding and stability. Proton and electron transfer are often coupled, as in almost all the steps of the mitochondrial respiratory chain. 

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In an extensive SFA study of protein receptor-ligand interactions, Leckband and co-workers [114] showed the importance of electrostatic, dispersion, steric, and hydrophobic forces in mediating the strong streptavidin-biotin interaction. Israelachvili and co-workers [66, 115] have measured the Hamaker constant for the dispersion interaction between phospholipid bilayers and find A = 7.5 1.5 X 10 erg in water. 

In this section the influence of micelles of cetyltrimethylammonium bromide (CTAB), sodium dodecylsulfate (SDS) and dodecyl heptaoxyethylene ether (C12E7) on the Diels-Alder reaction of 5.1a-g with 5.2 in the absence of Lewis-add catalysts is described (see Scheme 5.1). Note that the dienophiles can be divided into nonionic (5.1a-e), anionic (5.If) and cationic (5.1g) species. A comparison of the effect of nonionic (C12E7), anionic (SDS) and cationic (CTAB) micelles on the rates of their reaction with 5.2 will assess of the importance of electrostatic interactions in micellar catalysis or inhibition. 

The importance of electrostatic effects in protein structure and function has long been recognized (Tanford and Kirkwood, 1957 Peratz, 1978 Warshel and Russell, 1984 Rogers, 1989). It is generally believed that electrostatic field effects are among the first that come into play when two protein molecules approach each other. The reason for this is that electrostatic fields reach much further out than any other force fields that we associate with protein-protein interaction. It is reasonable to expect that motion in the combined electrostatic field of both molecules helps to orient the molecules for subsequent docking. 

Schmuck, C. (1999) Highly stable self association of 5-(guanidiniocarbonyl)-lH-pyrrole-2-carboxylate in DMSO - The importance of electrostatic interactions, Eur. J. Org. Chem. 9, 2397-2403. 

Cytosolic protein kinase C requires both Ca2+ and an acidic phospholipid for optimum in vitro (kinase) activity. Phosphatidylserine has been the phosphoglyceride of choice, and models have been constructed describing the importance of electrostatic interactions in the binding of phosphatidylserine to the kinase (or to a membrane). Also, it is suggested that the selective binding of phosphatidylserine in a cooperative manner is most important to the efficient formation of a fully activated complex. Much effort has been expended by many laboratories to prove the uniqueness of the phosphatidylserine effect. However, it would be of value to all investigators in this area to read a review by Nishizuka (1992), in which he explores the importance of other pathways (and lipids) to the activation of protein kinase C. 

Wong, S. S. Paddon-Row, M. N. The importance of electrostatic effects in controlling 7i-facial stereoselectivity in nucleophilic additions to carbonyl compounds An ab initio MO study of a prototype chelation model, J. Chem. Soc. Chem. Commun. 1991, 327-330. 

The question has been essentially decided by more recent experiments (Beychok and Steinhardt, 1959 Steinhardt et al., 1962). One procedure was to reduce the temperature and increase the ionic strength, the increase in ionic strength being for the purpose of diminishing the importance of electrostatic interactions. A second procedure was to use hemoglobin derivatives which are especially stable in the native state, these being the... 

Molecular mechanics (AMBER, Singh et al., 1986) was employed by the authors to study the effect of the whole system (protein + solvent) on the scissile bond in the Michaelis complex and in the TI. They find that interaction enthalpy is more favorable in the TI due to stabilization by the catalytic triad, by the oxyanion hole and by the environment, a total of 26 kcal/mol. The breakdown to interaction components demonstrates the importance of electrostatic stabilization of the TI. More reliable estimates of these interactions require free energy perturbations or related free energy methods. 

Esposito V, Gallucci R, Picone D, Saviano G, Tancredi T, Temussi PA (2006) The importance of electrostatic potential in the interaction of sweet proteins with the sweet taste receptor. J Mol Biol 360 448-456... 

The importance of electrostatics in the interaction of aromatics fluorine with cations and hydrogen bond donors can be visualized using electrostatic potential surfaces (Figure 20.37). In monofluorobenzene, the potential of the fluorine is concentrated on the unique fluorine present, whereas in polyfluorobenzene the negative charge is spread over several fluorine atoms. For this reason, monofluorobenzene may give stronger interactions. 

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