On the Charge Regulation of Proteins

Abstract

It is known that the overall charge of a protein can change as the molecule approaches a charged object like another protein or a cell membrane. We have formalized this mechanism using a statistical mechanical framework and show how this rather overlooked interaction increases the attraction between protein molecules. From the theory, we can identify a unique property, the protein charge capacitance, that contains all information needed to describe the charge regulation mechanism. The capacitance can be obtained from experiment or theory and is a function of pH, salt concentration, and the number of titrating residues. For a range of different protein molecules, we calculate the capacitance and demonstrate how it can be used to quantify the charge regulation interaction. With minimal effort, the derived formulas can be used to improve existing models by including a charge regulation term. Good agreement is found between theory, simulations, and experimental data.

Molecular evidence of stereo-specific lactoferrin dimers in solution

“…This software package has been applied with success for computation of the virial coefficient of lysozyme and binding constants of lysozyme and apo-α-lactalbumin. [13,14] The simulation procedure is described in detail in the Appendix as well as elsewhere and we shall give here only a brief overview [13,15]: Each protein is treated as a rigid body consisting of spherical amino acid beads that may be either charged or neutral, depending on the type and protonation state; PDB entry 1BLF was used to generate the coarse holo-Lactoferrin structure. A rigid model is reasonable since the structure of the holo-form is considered stiff and is resistant to proteolytic degradation.…”

“…This provides us with an estimate of the charge distribution of the proteins that are being used as input when we evaluate the pairinteraction. A complete description of simulation details and parameters can be found in the reference [13] and [15]. The radii of some of the different amino acids, along with pKa-values used to generate average charges, are provided in Table A.1.…”

A comparative analysis of the folding and misfolding pathways of the third PDZ domain of PSD95 investigated under different pH conditions

“…7). Nevertheless, when Glu residues titrate above pH 3 (pKa = 3.0-3.5) the proton release should generate some degree of electrostatic repulsion between the negative charges of the Glu side-chains, where the π-electron clouds of the aromatic rings might also contribute to this energy balance to some degree [24][25][26][27][28]. This phenomenon gives rise to an opening of the C-terminal α3 helix and of the β2-β3 region, as has also been shown by NMR [29].…”

Titratable macroions in multivalent electrolyte solutions: Strong coupling dressed ion approach

“…Charge regulation has been invoked and widely applied in the context of various colloidal systems: stability and inter-surface forces due to the electrostatic double-layers [7,25], dissociation of amino acids and the corresponding electrostatic protein-protein interactions [26,[28][29][30], charge regulation of protein aggregates and viral shells [31], and of polyelectrolytes and polyelectrolyte brushes [32][33][34][35], as well as charge regulation of charged lipid membranes [36][37][38]. Here, we specifically dedicate ourselves to the problem of the connection between charge regulation and electrostatic interactions between proteins in ionic solutions [1,27].…”