Frontier Applications of Experimental Charge Density and Electrostatics to Bio-macromolecules

Abstract

Experimental charge density methodologies have been extended to macromolecular structures and biocrystallography. Ultra-high resolution diffraction data can now be collected at third-generation synchrotron sources for well-ordered protein crystals. The molecular structure can then be refined using multipolar expansion of the atomic electron density, which is a more sophisticated model than the independent atom model (neutral spherical atoms). Several databases describing average electron densities in terms of multipolar atoms were built by different research groups. These library charge density parameters have been transferred, in the literature, to several small molecules and a few biomacromolecules. The construction of the molecular electron densities through database transfer yields a better crystallographic refinement, notably when the X-ray diffraction data are measured at atomic resolution (0.6–1 A). The use of an aspherical atom model for the electron density in atomic resolution protein structures allows for the accurate description of their electrostatic properties. The applications to several protein structures including syntenin PDZ2 domain, influenza neuraminidase, human aldose reductase (at 0.66 A resolution) and a DING phosphate binding protein have been reported.