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Physicochemical origin of high correlation between thermal stability of a protein and its packing efficiency: a theoretical study for staphylococcal nuclease mutants.

ABSTRACT: There is an empirical rule that the thermal stability of a protein is related to the packing efficiency or core volume of the folded state and the protein tends to exhibit higher stability as the backbone and side chains are more closely packed. Previously, the wild type and its nine mutants of staphylococcal nuclease were compared by examining their folded structures. The results obtained were as follows: The stability was not correlated with the number of intramolecular hydrogen bonds, intramolecular electrostatic interaction energy, or degree of burial of the hydrophobic surface; though the empirical rule mentioned above held, it was not the proximate cause of higher stability; and the number of van der Waals contacts N vdW, or equivalently, the intramolecular van der Waals interaction energy was an important factor governing the stability. Here we revisit the wild type and its nine mutants of staphylococcal nuclease using our statistical-mechanical theory for hydration of a protein. A molecular model is employed for water. We show that the pivotal factor is the magnitude of the water-entropy gain upon folding. The gain originates from an increase in the total volume available to the translational displacement of water molecules coexisting with the protein in the system. The magnitude is highly correlated with the denaturation temperature T m. Moreover, the apparent correlation between N vdW and T m as well as the empirical rule is interpretable (i.e., their physicochemical meanings can be clarified) on the basis of the water-entropy effect.

SUBMITTER: Oda K

PROVIDER: S-EPMC4736840 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Physicochemical origin of high correlation between thermal stability of a protein and its packing efficiency: a theoretical study for staphylococcal nuclease mutants.

Oda Koji K Kinoshita Masahiro M

Biophysics and physicobiology 20150731

There is an empirical rule that the thermal stability of a protein is related to the packing efficiency or core volume of the folded state and the protein tends to exhibit higher stability as the backbone and side chains are more closely packed. Previously, the wild type and its nine mutants of staphylococcal nuclease were compared by examining their folded structures. The results obtained were as follows: The stability was not correlated with the number of intramolecular hydrogen bonds, intramo ...[more]

PMID: 27493849

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Project description:To search for submolecular foldon units, the spontaneous reversible unfolding and refolding of staphylococcal nuclease under native conditions was studied by a kinetic native-state hydrogen exchange (HX) method. As for other proteins, it appears that staphylococcal nuclease is designed as an assembly of well-integrated foldon units that may define steps in its folding pathway and may regulate some other functional properties. The HX results identify 34 amide hydrogens that exchange with solvent hydrogens under native conditions by way of large transient unfolding reactions. The HX data for each hydrogen measure the equilibrium stability (Delta G(HX)) and the kinetic unfolding and refolding rates (k(op) and k(cl)) of the unfolding reaction that exposes it to exchange. These parameters separate the 34 identified residues into three distinct HX groupings. Two correspond to clearly defined structural units in the native protein, termed the blue and red foldons. The remaining HX grouping contains residues, not well separated by their HX parameters alone, that represent two other distinct structural units in the native protein, termed the green and yellow foldons. Among these four sets, a last unfolding foldon (blue) unfolds with a rate constant of 6 x 10(-6) s(-1) and free energy equal to the protein's global stability (10.0 kcal/mol). It represents part of the beta-barrel, including mutually H-bonding residues in the beta 4 and beta 5 strands, a part of the beta 3 strand that H-bonds to beta 5, and residues at the N-terminus of the alpha2 helix that is capped by beta 5. A second foldon (green), which unfolds and refolds more rapidly and at slightly lower free energy, includes residues that define the rest of the native alpha2 helix and its C-terminal cap. A third foldon (yellow) defines the mutually H-bonded beta1-beta2-beta 3 meander, completing the native beta-barrel, plus an adjacent part of the alpha1 helix. A final foldon (red) includes residues on remaining segments that are distant in sequence but nearly adjacent in the native protein. Although the structure of the partially unfolded forms closely mimics the native organization, four residues indicate the presence of some nonnative misfolding interactions. Because the unfolding parameters of many other residues are not determined, it seems likely that the concerted foldon units are more extensive than is shown by the 34 residues actually observed.

Dataset Information

Physicochemical origin of high correlation between thermal stability of a protein and its packing efficiency: a theoretical study for staphylococcal nuclease mutants.

Publications

Physicochemical origin of high correlation between thermal stability of a protein and its packing efficiency: a theoretical study for staphylococcal nuclease mutants.

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