Ah. Juffer et al., CALCULATING ACID-DISSOCIATION CONSTANTS OF PROTEINS USING THE BOUNDARY-ELEMENT METHOD, JOURNAL OF PHYSICAL CHEMISTRY B, 101(38), 1997, pp. 7664-7673
The boundary element method (BEM) in combination with continuum electr
ostatics is employed to compute the acid-dissociation constants K-a (p
K(a)= -log K-a) of titrating sites in proteins. The boundary element m
ethod determines the electrostatic potential from the solution of two
coupled integral equations, valid on a triangulated surface enclosing
the macromolecule. First the intrinsic pK(2)(intr) is computed from th
e shift of the pK(a) of a model compound containing the titrating site
upon its transfer from solution to the protein; during this step inte
ractions between titrating sites are neglected. Subsequently, interact
ions between titrating sites are included by means of a Monte Carlo sc
heme to sample protonation states of the protein. A convenient vector-
matrix formulation in terms of the BBM is given which allows the use o
f a single atom or a detailed charge model (or a combination of both)
to describe the titrating sites. The method has been applied to four p
roteins: bovine pancreatic trypsin inhibitor, calbindin, lysozyme, and
ovomucoid third-domain. Different choices for the dielectric constant
of proteins ranging from 4 to 78.5 were investigated in a systematic
fashion. Comparisons are made with pK(a) values calculated by the fini
te difference method and those determined experimentally for these fou
r proteins. Our results indicate that accurate pK(a) values are obtain
ed with the BEM when a dielectric constant for the protein of 20 or hi
gher is used, For calbindin, different choices for the ionic strength
were considered and comparison was made with pK(a) values obtained exp
erimentally and from a simulation model using explicit ions for the so
lvent.