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Center For Applied and Computational Mathematics

Charge Regulation of Proteins

Charge regulation of proteins
Faculty: George Thurston
  David Ross
  Tony Harkin
  Chris Wahle


We study the electrostatic contribution to the effective potential between two spherical low-dielectric particles that carry proton-titratable sites within a linearized setting. To evaluate the needed work of charging for each possible proton occupancy configuration, together with its crucial dependence on sphere separation, we numerically solve a coarse-grained linear Debye-Huckel model that incorporates nonuniform dielectric and ionic solution properties at a series of intersphere separations and for chosen titratable charge locations on each sphere. We combine the resulting work-of-charging matrix with site-specific chemical potentials of proton binding to construct the Boltzmann-weighted probabilities of each possible occupancy pattern of the titratable sites as functions of intersphere separation. With the use of these probabilities we find that a nonmonotonic average electrostatic potential can result that is repulsive at larger sphere separations but attractive at close separations. The nonmonotonic potential corresponds to particular choices of site-specific unoccupied charge values and their corresponding proton affinities, and its occurrence is dependent on pH in relation to the pKa values of the titratable groups. For the chosen titratable groups, we identify the particular change from repulsive to attractive proton occupancy patterns with decreasing intersphere separation that gives rise to the modeled nonmonotonic dependence and derive more general conditions under which such a nonmonotonic dependence can occur. Within the present model we find that stationary points of the charge-regulated average electrostatic potential, considered as a function of intersphere separation, occur when a normalized Boltzmann-averaged intersphere charge number product equals its covariance with an average free energy of charging divided by kBT. We derive more general conditions for the location and nature of critical points in the electrostatic intersphere potential, which are not dependent on the validity of the present linear model. Analysis of the present simple prototype model can be a helpful step toward developing a framework for predicting when (i) patterned charge-regulated occupancy patterns, (ii) orientation-dependent attractions due to relatively fixed heterogeneous charging patterns, and (iii) screened net protein charge could separately dominate the electrostatic portion of the interactions between model biological macromolecules and other nanoparticles.


  1. Model for Evaluating the Patterned Charge Regulation Contribution to Electrostatic Interactions between Low Dielectric Spheres, Hollenbeck, D., Martini, K. M., Langner, A., Harkin, A., Ross, D. S., and Thurston, G. M., Phys. Rev. E, 82, 031402, 2010.


Dawn Hollenbeck (RIT)