A volumetric method for representing and comparing regions of electrostatic focusing in molecular structure

Abstract

Algorithms for protein structure comparison employ diverse and effective representations of molecular shape. However, they do not generally represent the shape of the electrostatic potential field, except at the molecular surface. This approach neglects the geometry of the field on the outside of the molecular surface, where electrostatic focusing can play an important role in molecular recognition: Narrow clefts and grooves can partially shield charged atoms from the high dielectric solvent, enhancing potentials inside the cavity and projecting the lines of the electric field outwards from the cavity. This interplay between molecular shape and electrostatic potential is an essential means of recognition in many biomolecular systems. To leverage this phenomenon for more accurate protein structure comparison algorithms, this paper presents the first comparative representation of the region where focusing occurs. We first verified our representation in a case study of superoxide dismutase, where electrostatic focusing was first observed. Our method accurately identified the site where electrostatic focusing was established in the past. We then applied our representation to compare regions of electrostatic focusing with the positions of charged amino acids, to determine where they coincide. Over 866 protein-DNA complexes, our representations correctly detected the enrichment of arginines that contact regions of electrostatic focusing in the minor grooves of DNA. These results indicate that our novel methods precisely represent and accurately compare regions where electrostatic focusing occurs. They also describe a novel and elegant technique for seamlessly integrating molecular shape and electrostatic focusing into the same structure comparison framework. Figure 1: Boolean Set operations on three dimensional solids (left) can detect regions where two solids coincide (intersection), where either solid occupies space (union), or regions inside one solid and not inside the other (difference).

Isolating Influential Regions of Electrostatic Focusing in Protein and DNA Structure

“…In this section, we first paraphrase our earlier results that demonstrate the accuracy of our methods for identifying regions of electrostatic focusing [11]. In sections 4.1 and 4.2, we show that our methods identify previously documented regions of electrostatic focusing in protein, on a small scale, and DNA, on a large scale.…”

“…In earlier work, we demonstrated that three dimensional solids could be used to represent and compare regions of electrostatic focusing [11]. Applying this approach to the analysis of protein and DNA structures, we verified, using Boolean set operations [10] (Figure 1), that it correctly identified focusing regions, in proteins and DNA, discussed in the literature.…”

“…In earlier work [11], we described a method for representing the region of electrostatic focusing. To evaluate this method on a large scale using DNA structures, we also developed a technique for finding amino acids in contact with the minor groove in DNA, and evaluating their position relative to the focusing region.…”