Electrostatic potential, molecular interactive noncovalent interactions

The use of the electrostatic potential in analyzing and predicting molecular interactive behavior and properties has increased remarkably over the past 25 years. In 1980, it was still reasonable to hope to at least mention, in one lengthy review chapter (Politzer and Daiker 1981), all of the papers that had been published in this area. In 1996, such an objective would be ridiculous. This popularity can be attributed to (a) the insight that V(r) can provide, especially into noncovalent interactions, and (b) the widespread availability of computational software packages of which it has become a standard feature. 

Murray, J. S., K. Paulsen, and P. Politzer. 1994. Molecular Surface Electrostatic Potentials on the Analysis of Non-Hydrogen-Bonding Noncovalent Interactions. Proc. Ind. Acad. Sci. (Chem. Sci.) 106, 267. 

The final part is devoted to a survey of molecular properties of special interest to the medicinal chemist. The Theory of Atoms in Molecules by R. F.W. Bader et al., presented in Chapter 7, enables the quantitative use of chemical concepts, for example those of the functional group in organic chemistry or molecular similarity in medicinal chemistry, for prediction and understanding of chemical processes. This contribution also discusses possible applications of the theory to QSAR. Another important property that can be derived by use of QC calculations is the molecular electrostatic potential. J.S. Murray and P. Politzer describe the use of this property for description of noncovalent interactions between ligand and receptor, and the design of new compounds with specific features (Chapter 8). In Chapter 9, H.D. and M. Holtje describe the use of QC methods to parameterize force-field parameters, and applications to a pharmacophore search of enzyme inhibitors. The authors also show the use of QC methods for investigation of charge-transfer complexes. 

The quantities defined by Eqs. (2)—(7) plus Vs max, Vs min, and the positive and negative areas, A and, enable detailed characterization of the electrostatic potential on a molecular surface. Over the past ten years, we have shown that subsets of these quantities can be used to represent analytically a variety of liquid-, solid-, and solution-phase properties that depend on noncovalent interactions [14-17, 84] these include boiling points and critical constants, heats of vaporization, sublimation and fusion, solubilities and solvation energies, partition coefficients, diffusion constants, viscosities, surface tensions, and liquid and crystal densities. 

The quantities that have been presented do effectively characterize the electrostatic potential on a molecular surface. We have shown that a number of macroscopic, condensed-phase properties that depend upon noncovalent interactions can be expressed in terms of some subset of these quantities (frequently... 

J.S. Murray et al., Molecular surface electrostatic potentials in the analysis of non-hydrogen-bonding noncovalent interactions. Proc. Indian Acad. Sci. 106, 267-275 (1994)... 

J.S. Murray, P. Politzer, Statistical analysis of the molecular surface electrostatic potential An approach to describing noncovalent interactions in condensed phases. J. Mol. Struct. (Theo-chem) 425, 107-114 (1998)... 

In a series of studies, reviewed on several occasions [13,88,89], we have found that a variety of physical properties that depend upon noncovalent interactions, including AHvap and AHsub, can be related quantitatively to certain features of the electrostatic potentials on molecular surfaces. The electrostatic potential V(r) that the electrons and nuclei of a molecule create at any point r is given by,... 

A general method, proposed by Politzer and coworkers, to estimate physico-chemical properties depending on noncovalent interactions [Brinck et ai, 1993 Murray et al., 1993 Politzer etal., 1993 Murray et al., 1994]. This is based on molecular surface area in conjunction with some statistically-based quantities related to the - molecular electrostatic potential (MEP) at the - molecular surface. The electron isodensity contour surface [0.001 a.u. contour of Q(r)j is taken as the molecular surface model. 

Murray, J.S. and Politzer, P. (1998). Statistical Analysis of the Molecular Surface Electrostatic Potential An Approach to Describing Noncovalent Interactions in Condensed Phases. J.Mol. Struct.(Theochem), 425,107-114. 

Halogen bonding also manifests itself in the relative orientations of halogen derivatives in the crystalline state [149]. Indeed, the modes of interaction in many nonhydrogen-bonded noncovalent systems, ranging from gas phase complexes to molecular crystals, can be satisfactorily rationalized in terms of molecular surface electrostatic potentials [44,55,150]. In several instances, we have used this approach to explain anomalously high measured solid densities [151,152]. 

Another very important type of noncovalent interaction is that between solutes and solvents. We have developed GIPF relationships in which the free energies of solvation in seven different solvents, with various polarities, are expressed in terms of quantities characterizing the solute s molecular surface electrostatic potentials [153,154]. However, there have been many more elaborate treatments that explicitly evaluate the energy of the interaction between the solute and the solvent the latter may be described, e.g., as a dielectric continuum, as a fixed lattice, or in terms of individual molecules. Detailed accounts can be found in several reviews [23,155-158]. 

Politzer P, Murray JS, Peralta-Inga Z. Molecular surface electrostatic potentials in relation to noncovalent interactions in biological systems. Int J Quantum Chem 2001 85 676-684. 

The belief that electrostatic (Coulomb) interactions exhibit little directionality (i.e., that their energy hardly depends on the bond angle) is widespread. This is because the concept of net atomic charges (atom-centered monopoles) has become ingrained in chemists thinking, so that Coulomb interactions with a polar atom are believed to be necessarily isotropic and directionahty of Coulomb interactions only to be the result of secondary interactions with more distant atoms. Neither of these assumptions is correct and the reasons have been known for decades. Nonetheless, directionality in noncovalent interactions is still often attributed to covalent contributions or donor-acceptor interactions because the Coulomb interaction is believed not to be able to give rise to significant directionality. The purpose of this chapter is to discuss Coulomb interactions with special emphasis on directionality and anisotropy of the molecular electrostatic potential (MEP) [1] around atoms. 

Murray, J. S. Politzer, P. 2009. Molecular surfaces, van der Waals radii and electrostatic potentials in relation to noncovalent interactions. Croat. Chem. Acta 82 267-275. 

---