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Electrostatic properties of protein-protein complexes.

ABSTRACT: Statistical electrostatic analysis of 37 protein-protein complexes extracted from the previously developed database of protein complexes (ProtCom, http://www.ces.clemson.edu/compbio/protcom) is presented. It is shown that small interfaces have a higher content of charged and polar groups compared to large interfaces. In a vast majority of the cases the average pKa shifts for acidic residues induced by the complex formation are negative, indicating that complex formation stabilizes their ionizable states, whereas the histidines are predicted to destabilize the complex. The individual pKa shifts show the same tendency since 80% of the interfacial acidic groups were found to lower their pKas, whereas only 25% of histidines raise their pKa upon the complex formation. The interfacial groups have been divided into three sets according to the mechanism of their pKa shift, and statistical analysis of each set was performed. It was shown that the optimum pH values (pH of maximal stability) of the complex tend to be the same as the optimum pH values of the complex components. This finding can be used in the homology-based prediction of the 3D structures of protein complexes, especially when one needs to evaluate and rank putative models. It is more likely for a model to be correct if both components of the model complex and the entire complex have the same or at least similar values of the optimum pH.

SUBMITTER: Kundrotas PJ

PROVIDER: S-EPMC1544298 | biostudies-literature | 2006 Sep

REPOSITORIES: biostudies-literature

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Electrostatic properties of protein-protein complexes.

Kundrotas Petras J PJ Alexov Emil E

Biophysical journal 20060616 5

Statistical electrostatic analysis of 37 protein-protein complexes extracted from the previously developed database of protein complexes (ProtCom, http://www.ces.clemson.edu/compbio/protcom) is presented. It is shown that small interfaces have a higher content of charged and polar groups compared to large interfaces. In a vast majority of the cases the average pKa shifts for acidic residues induced by the complex formation are negative, indicating that complex formation stabilizes their ionizabl ...[more]

PMID: 16782791

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Project description:Human uracil DNA glycosylase (hUNG) follows an extended reaction coordinate for locating rare uracil bases in genomic DNA. This process begins with diffusion-controlled engagement of undamaged DNA, followed by a damage search step in which the enzyme remains loosely associated with the DNA chain (translocation), and finally, a recognition step that allows the enzyme to efficiently bind and excise uracil when it is encountered. At each step along this coordinate, the enzyme must form DNA interactions that are highly specialized for either rapid damage searching or catalysis. Here we make extensive measurements of hUNG activity as a function of salt concentration to dissect the thermodynamic, kinetic, and electrostatic properties of key enzyme states along this reaction coordinate. We find that the interaction of hUNG with undamaged DNA is electrostatically driven at a physiological concentration of potassium ions (ΔGelect = -3.5 ± 0.5 kcal mol(-1)), with only a small nonelectrostatic contribution (ΔGnon = -2.0 ± 0.2 kcal mol(-1)). In contrast, the interaction with damaged DNA is dominated by the nonelectrostatic free energy term (ΔGnon = -7.2 ± 0.1 kcal mol(-1)), yet retains the nonspecific electrostatic contribution (ΔGelect = -2.3 ± 0.2 kcal mol(-1)). Stopped-flow kinetic experiments established that the salt sensitivity of damaged DNA binding originates from a reduction of kon, while koff is weakly dependent on salt. Similar findings were obtained from the salt dependences of the steady-state kinetic parameters, where the diffusion-controlled kcat/Km showed a salt dependence similar to kon, while kcat (limited by product release) was weakly dependent on salt. Finally, the salt dependence of translocation between two uracil sites separated by 20 bp in the same DNA chain was indistinguishable from that of kon. This result suggests that the transition-state for translocation over this spacing resembles that for DNA association from bulk solution and that hUNG escapes the DNA ion cloud during translocation. These findings provide key insights into how the ionic environment in cells influences the DNA damage search pathway.

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Electrostatic properties of protein-protein complexes.

Publications

Electrostatic properties of protein-protein complexes.

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