Electrostatic potential molecular surfaces.

Abstract

Color-coded computer graphics representations of the electrostatic potentials of trypsin, trypsin-inhibitor, prealbumin and its thyroxine complex, fragments of double-helical DNA, and a netropsin-DNA complex illustrate the electrostatic and topographic complementarity in macromolecule-ligand interactions. This approach is powerful in revealing intermolecular specificity and shows promise of having predictive value in drug design.The electrostatic potential is a powerful tool that has provided insights into intermolecular association and molecular properties of small molecules (1), actions of drug molecules and their analogs (2), the biological function of hemoglobin (3), and enzyme catalysis (4). We thought that, given the electrostatic potentials ofboth a ligand and its receptor, much greater progress might be made in the "rational design" of the optimal ligand (5-7). Subsequent studies of the electrostatic potentials of macromolecules (8-10) demonstrate the feasibility ofthis approach, but there has been no satisfactory way to represent the electrostatic potential in a way useful for understanding electrostatic complementarity. This problem is effectively solved by displaying the electrostatic potential molecular surface with a realtime interactive color graphics facility (11) using the molecular surface definition of Richards (12) What should one use for the ionization state ofexposed acidic and basic residues (9)? An assumption that all residues are in their predominant state of ionization in aqueous solution at pH 7 exaggerates the importance of the charged residues, whereas an assumption of neutrality ignores the effects of the charged groups. Here we adopt the following compromise: for protein calculations the charges were retained, and for nucleic acids we either explicitly included counterions or neutralized the phosphate charges.The molecular surfaces for each structure were calculated from x-ray and energy-refined coordinates (19-21) by using the program MS (22). The electrostatic potential was calculated 1.4 A along the surface normal vector from a given molecular surface point and represented at the surface point itself. We calculated the contribution of each atom within 20 A of the electrostatic potential point F and used the method of neutral spheres (23, 24), which corrects for dipoles split by the finite cutoff radius by adding an additional interaction (at that radius) to ensure that the net charge inside the sphere is zero. The surfaces were displayed at the University of California (San Francisco) Computer Graphics Laboratory with the display program HANDLE (written by M. Connolly). RESULTSTrypsin-Trypsin Inhibitor. First we consider the prototype protein-protein interaction of trypsin and bovine pancreatic trypsin inhibitor (BPTI) (25). There is a large negative pocket (due to in trypsin that is the binding pocket for the positively charged Lys-15 on the lower right of BPTI (Fig.

Average local ionization energies on the molecular surfaces of aromatic systems as guides to chemical reactivity

“…that are unique to a molecule. This means of designating a molecular surface is in contrast to earlier methods in which it has been defined as the outer surface of a set of intersecting spheres centered on the nuclei of the molecule (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22); such surfaces cannot take into account the very properties that are characteristic of a molecule.…”

High-resolution Digital Mapping of N-Methylpurines in Human Cells Reveals Modulation of Their Induction and Repair by Nearest-neighbor Nucleotides

“…The effects of the 3Ј neighbor nucleotides on the 7MeG induction may also be due to modulation of the electrostatic potential. It can be predicted that the electrostatic potential at the N 7 position of a G can be reinforced by a 3Ј-G or -T (19,20).…”

Cationic porphyrins as probes of DNA structure

“…Theoretical calculations by Kollman and Pullman and their coworkers (25,26) have shown that although many factors can influence the outcome of the calculations, the surface of the minor groove of AT rich regions of DNA possesses a high negative potential. Thus, the AT specificity observed for all of the compounds studied may be related to strong electrostatic attractive forces between them and the dipoles located on adenine and thymine in the minor groove of DNA.…”