Optimization of the electrostatic interactions in proteins of different functional and folding type

Abstract

The 3-dimensional optimization of the electrostatic interactions between the charged amino acid residues was studied by Monte Carlo simulations on an extended representative set of 141 protein structures with known atomic coordinates. The proteins were classified by different functional and structural criteria, and the optimization of the electrostatic interactions was analyzed. The optimization parameters were obtained by comparison of the contribution of charge-charge interactions to the free energy of the native protein structures and for a large number of randomly distributed charge constellations obtained by the Monte Carlo technique. On the basis of the results obtained, one can conclude that the charge-charge interactions are better optimized in the enzymes than in the proteins without enzymatic functions. Proteins that belong to the mixed cr/3 folding type are electrostatically better optimized than pure cu-helical or /3-strand structures. Proteins that are stabilized by disulfide bonds show a lower degree of electrostatic optimization. The electrostatic interactions in a native protein are effectively optimized by rejection of the conformers that lead to repulsive charge-charge interactions. Particularly, the rejection of the repulsive contacts seems to be a major goal in the protein folding process. The dependence of the optimization parameters on the choice of the potential function was tested. The majority of the potential functions gave practically identical results. Keywords: energy calculations; ion pairs; Monte Carlo simulations; potential functions; protein electrostatics; protein foldingThe nature and spatial distribution of charged residues in a folded protein can be considered as an evolutionary solution of 2 different tasks: first, the stabilization of the native structure by the contribution of the electrostatic interactions to the free energy and, second, the display of a functional role by creating a specific electrostatic field, necessary for the enhancement of the enzymatic reactions, intermolecular recognition, and assembly. In principle, the solution of the second task could be opposite to the stabilization effect. The magnitude of the stabilization effect of the other forces governing protein folding could counteract the necessity of significant electrostatic interactions.

Electrostatic coupling to pH‐titrating sites as a source of cooperativity in protein‐ligand binding

“…In molecular mechanics calculations, the use of distancedependent dielectric constants proportional to the charge separation amounts to an inverse-square law (Brooks et al, 1983). An inverse-square law has been found to give a good account of the evolutionary optimization of electrostatic interactions in proteins (Spassov et al, 1994). It also gives a reasonable fit to finitedifference solutions to the Poisson equation in the MEAD model (V. Spassov & D. Bashford, unpubl.…”

Protein Ionizable Groups: pK Values and Their Contribution to Protein Stability and Solubility

“…However, the arrangement is more favorable on some proteins than on others and is sometimes unfavorable (28). Studies of the pH dependence of protein stability show that coulombic interactions do not make a large contribution to protein stability, probably at most 10 kcal/mol (29).…”

Engineering Hyperthermostability into a GH11 Xylanase Is Mediated by Subtle Changes to Protein Structure

“…Although significant stabilization by charged residues at the surface of proteins is often due to saltbridge formation (34 -36), it has been shown that optimum placing of individual charged surface residues in the overall electrostatic network provides a general model for hyperthermophilic protein stability (37)(38)(39). It remains possible that, because desolvation of charged side chains is destabilizing, the introduced charge may enforce surface exposure during refolding, stabilizing the loop connecting ␤-strands 4 and 5 (Glu-35 is at the very end of ␤-strand 4) and improving the cooperativity of the folding pathways (40).…”