Atoms‐in‐molecules study of the genetically encoded amino acids. III. Bond and atomic properties and their correlations with experiment including mutation‐induced changes in protein stability and genetic coding
Authors: Matta Chérif F. , Bader Richard F. W. 
Published: July 2003

AbstractThis article presents a study of the molecular charge distributions of the genetically encoded amino acids (AA), one that builds on the previous determination of their equilibrium geometries and the demonstrated transferability of their common geometrical parameters. The properties of the charge distributions are characterized and given quantitative expression in terms of the bond and atomic properties determined within the quantum theory of atoms‐in‐molecules (QTAIM) that defines atoms and bonds in terms of the observable charge density. The properties so defined are demonstrated to be remarkably transferable, a reflection of the underlying transferability of the charge distributions of the main chain and other groups common to the AA. The use of the atomic properties in obtaining an understanding of the biological functions of the AA, whether free or bound in a polypeptide, is demonstrated by the excellent statistical correlations they yield with experimental physicochemical properties. A property of the AA side chains of particular importance is the charge separation index (CSI), a quantity previously defined as the sum of the magnitudes of the atomic charges and which measures the degree of separation of positive and negative charges in the side chain of interest. The CSI values provide a correlation with the measured free energies of transfer of capped side chain analogues, from the vapor phase to aqueous solution, yielding a linear regression equation withr2= 0.94. The atomic volume is defined by the van der Waals isodensity surface and it, together with the CSI, which accounts for the electrostriction of the solvent, yield a linear regression (r2= 0.98) with the measured partial molar volumes of the AAs. The changes in free energies of transfer from octanol to water upon interchanging 153 pairs of AAs and from cyclohexane to water upon interchanging 190 pairs of AAs, were modeled using only three calculated parameters (representing electrostatic and volume contributions) yielding linear regressions withr2values of 0.78 and 0.89, respectively. These results are a prelude to the single‐site mutation‐induced changes in the stabilities of two typical proteins: ubiquitin and staphylococcal nuclease. Strong quadratic correlations (r2∼ 0.9) were obtained between ΔCSI upon mutation and each of the two terms ΔΔHandTΔΔS taken from recent and accurate differential scanning calorimetry experiments on ubiquitin. When the two terms are summed to yield ΔΔG, the quadratic terms nearly cancel, and the result is a simple linear fit between ΔΔGand ΔCSI withr2= 0.88. As another example, the change in the stability of staphylococcal nuclease upon mutation has been fitted linearly (r2= 0.83) to the sum of a ΔCSI term and a term representing the change in the van der Waals volume of the side chains upon mutation. The suggested correlation of the polarity of the side chain with the second letter of the AA triplet genetic codon is given concrete expression in a classification of the side chains in terms of their CSI values and their group dipole moments. For example, all amino acids with a pyrimidine base as their second letter in mRNA possess side‐chain CSI ≤ 2.8 (with the exception of Cys), whereas all those with CSI > 2.8 possess an purine base. The article concludes with two proposals for measuring and predicting molecular complementarity: van der Waals complementarity expressed in terms of the van der Waals isodensity surface and Lewis complementarity expressed in terms of the local charge concentrations and depletions defined by the topology of the Laplacian of the electron density. A display of the experimentally accessible Laplacian distribution for a folded protein would offer a clear picture of the operation of the “stereochemical code” proposed as the determinant in the folding process. Proteins 2003;52:360–399. © 2003 Wiley‐Liss, Inc.