SOME PROTEIN PROPERTIES IMPORTANT FOR ENZYME CATALYSIS - New Trends in Enzyme Catalysis and Biomimetic Chemical Reactions - page 149

4.2. Electrostatic effects in proteins and enzymes

Electrostatic interactions play a key role in the structure and function of biological
molecules. The association of proteins in solution and in membranes, protein-nucleic
acids and nucleic acid - nucleic acid interactions, enzyme-substrate complexation,
chemical reactions in enzyme active sites, charge-transfer, voltage gating of membrane
channels, folding and unfolding processes of biopolymers, etc., are all drastically
affected by the strength and distribution of the electrostatic field around various regions
in biological molecules. At one time or another, much of the wide methodological and
theoretical arsenal of chemical physics has been used to study electrostatic interactions
in biological and chemical systems.

4.2.1. THEORETICAL CALCULATIONS

Significant progress has been achieved in the theoretical calculation of these interactions.
The most advanced theoretical approach to the problem relies upon the use of the
Poisson-Debye equation for polarizable solutes of known structure embedded in a
dielectric medium (Klapper et al., 1986; Sharp and Honig, 1990; Bashford and Karplus,
1990; Bajorath et al., 1991, Aqvist et al., 1991; Tidor and Karplus,1991; Sharp et al.,
1992; Gilson, 1993; Loewenthal et al., 1993; Yang et al., 1993; Scott et al., 1994; Anni
et al., 1994, Hecht et al., 1995; Honig and Nicholls, 1995;
For the classical treatment of electrostatic interaction in solution the Poison-
Boltzman equation (PBS) is commonly used

where is the dimensionless electrostatic potential in units q is the charge,
is the static dielectric constant, p is the fixed charge density, and (I is
the ionic strength). denotes the position vector. In the accepted model, one supposes the
existence of two dielectric continuums: one of low dielectric constant for solutes

and one of high for the surrounding bulk aqueous phase. The main problem

is the choice of the value for different portions of such a complex mosaic system as

biopolymers.
To illustrate results of the theoretical calculation of electrostatic potential in proteins,
we will consider some typical examples. A macroscopic electrostatic model is used to
calculate the pKa values of the specific titratable groups in lysozyme (Bashford and
Karplus, 1990). The model makes use of detailed structural information. The solvation
self-energies and interactions between permanent partial charges and titratable charges
are considered. According to (Bajorath et al., 1991) Escherichia coli dihydrofolate
reductase (DHFR) carries a net charge of -10 electrons. Yet it binds ligands with net
charges of -4 (NADPH) and -2 (folate or dihydrofolate). The results show that the
enzyme is covered by an overall negative potential except for the ligand binding sites.
These sites are located inside a cavity of positive potential that enables the enzyme to
bind the negatively charged ligands. This property contributes significantly to electronic