Dielectric relaxation in proteins: Microscopic and macroscopic models

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 relax ation and nonrelaxation ("static") components of the free energy were calcu lated for charge insertion in the active site. The assumption of linear res ponse leads to a linear relation between the static and relaxation free ene rgies. This relation was verified by continuum calculations if and only if different protein dielectric constants were used for the static and relaxat ion components of the free energy; namely one for the static free energy an d 4-8 for the relaxation free energy. These were also the only values that gave at least fair agreement with molecular dynamics estimates df the free energy for this process. Applications of continuum models to other systems and more complex processes, such as ligand binding or calculation of titrat ion curves, are discussed briefly. (C) 1999 John Wiley & Sons, Inc.