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Q Rev Biophys. 1996 Feb;29(1):1-90.

Roles of electrostatic interaction in proteins.

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Protein Engineering Research Institute, Osaka, Japan.


More than 60 years after the analyses by Linderstrom-Lang and Kirkwood of their hypothetical 'protein' structures, we have now a plethora of experimental evidence and computational estimates of the electrostatic forces in proteins, with very many protein 3D structures at atomic resolution. In the mean time, there were in the beginning, many arguments and suggestions about the roles of electrostatics, mainly from empirical findings and tendencies. A few experimental results indicated that the electrostatic contribution is of the order of several kcal/mol, which was theoretically difficult to reproduce correctly, because a large opposing reaction field should be subtracted from a large, direct Coulombic field. Although the importance of the reaction field was recognized even 70 years ago, appropriate applications to protein molecules were made only in this decade, with the development of numerical computation. Now, an electrostatic molecular surface is one of the most popular pictures in journals of structural biology, indicating that the electrostatic force is one of the important components contributing to molecular recognition, which is a major focus of current biology and biochemistry. The development of NMR techniques has made it possible to observe the individual ionizations of ionizable groups in a protein, in addition to the determination of the 3D structure. Since it does not require any additional probe, each charge state can report the very local and heterogeneous electrostatic potentials working in the protein, without disturbing the original field. From the pKa values, the contributions of electrostatic interactions, ion pairs, charge-dipole interactions, and hydrogen bonds to protein stability have been correctly evaluated. Protein engineering also provides much more information than that obtainable from the native proteins, as the residues concerned can now be easily substituted with other amino acid residues having electrostatically different characteristics. Those experimental results have revealed smaller contributions than previously expected, probably because we underestimated the reaction field effects. Especially, a single ion pair stabilizes a protein only slightly, although a cooperative salt-bridge network can contribute significantly to protein stability. Marginal stabilities of proteins arise from small difference between many factors with driving and opposing forces. In spite of the small contribution of each single electrostatic interaction to the protein stability, the sum of their actions works to maintain the specific 3D structure of the protein. The 'negative' roles of electrostatics, which might destabilize protein conformation, should be pointed out. Unpaired buried charges are energetically too expensive to exit in the hydrophobic core. Isolated hydrogen bond donors and acceptors also exert negative effects, but they are not as expensive as the unpaired buried charges, with costs of a few kcal/mol. Therefore, statistical analyses of protein 3D structures reveal only rare instances of isolated hydrogen bond donors and acceptors. This must be the main reason why alpha-helices and beta-sheets are only observed in protein cores as the backbone structures. Such secondary structures do not leave any backbone hydrogen donors or acceptors unpaired, because of their intrinsically regular packing. Otherwise, it might be very difficult to construct a backbone structure, in which all the backbone amide and carbonyl groups had their own hydrogen bond partners in the protein core. There are two theoretical approaches to protein electrostatics, the macroscopic or continuum model, and the microscopic or molecular model. As described in this article, the macroscopic model has inherent problems because the protein-solvent system is very hetergeneous from the physical point of view...

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