Dielectric relaxation in response to charge separation or transfer is a cru
cial component of protein electrostatics. Theoretical studies can give valu
able insights; for example, they allow a separate analysis of protein and s
olvent relaxation. We review recent theoretical studies performed with macr
oscopic and microscopic models. Macroscopic continuum models provide a simp
le framework in which to interpret the results of detailed molecular dynami
cs simulations of dielectric relaxation. They are also widely used in prote
in modeling. Molecular dynamics simulations allow the Frohlich-Kirkwood die
lectric constant of a protein to be calculated. This dielectric constant is
a linear response coefficient, which is appropriate in principle to descri
be protein relaxation in response to perturbing fields and charges. The int
ernal dielectric constant of several proteins was found to be small (2-3),
while the overall dielectric constant is large (15-25) due to motions of ch
arged side chains at the protein surface. Poisson calculations using the lo
w internal dielectric constant of cytochrome c reproduced approximately mol
ecular dynamics relaxation free energies for charge insertion at multiple s
ites within this protein. In the protein aspartyl-tRNA synthetase, the rela
xation and nonrelaxation ("static") components of the free energy were calc
ulated for charge insertion in the active site. The assumption of linear re
sponse leads to a linear relation between the static and relaxation free en
ergies. This relation was verified by continuum calculations if and only if
different protein dielectric constants were used for the static and relaxa
tion components of the free energy; namely one for the static free energy a
nd 4-8 for the relaxation free energy. These were also the only values that
gave at least fair agreement with molecular dynamics estimates of the free
energy for this process. Applications of continuum models to other systems
and more complex processes, such as ligand binding or calculation of titra
tion curves, are discussed briefly. (C) 1999 John Wiley & Sons, Inc.