Very fast empirical prediction and rationalization of protein pK_a values

Abstract

A very fast empirical method is presented for structure-based protein pKa prediction and rationalization. The desolvation effects and intra-protein interactions, which cause variations in pKa values of protein ionizable groups, are empirically related to the positions and chemical nature of the groups proximate to the pKa sites. A computer program is written to automatically predict pKa values based on these empirical relationships within a couple of seconds. Unusual pKa values at buried active sites, which are among the most interesting protein pKa values, are predicted very well with the empirical method. A test on 233 carboxyl, 12 cysteine, 45 histidine, and 24 lysine pKa values in various proteins shows a root-mean-square deviation (RMSD) of 0.89 from experimental values. Removal of the 29 pKa values that are upper or lower limits results in an RMSD = 0.79 for the remaining 285 pKa values.

Does molecular docking reveal alternative chemopreventive mechanism of activation of oxidoreductase by sulforaphane isothiocyanates?

“…The protein structure was prepared for docking as described previously. This included the addition of missing hydrogens, protein solvatation, the 4 calculation of the atomic partial charges (AMBER99) and the protonation of the protein at physiological pH 7.4 using the PROPKA related method [27].…”

Development of constant-pH simulation methods in implicit solvent and applications in biomolecular systems

“…Differences between the theoretical treatments can also be seen in the manner the solvent is described and/or the numerical method applied to solve a given model. Empirical methods such as PROPKA, (Li et al 2005;Olsson et al 2011) Vriend's method (Krieger et al 2006) and the Burger & Ayers predictor (Burger and Ayers 2011) that have introduced plausible contributions in this field especially for high-throughput uses should also be mentioned here. Table 1 summarizes the main theoretical contributions to develop these classical effective CpH simulation methods that are also cited together with them as a function of the year of the published original works.…”

“…It was the beginning of the Poisson-Boltzmann (PB) equation era in biophysics and biochemistry. The pioneering and landmark work of this "new" approach for macromolecules represented at atomistic level and nonuniform dielectrics (in implicit solvent) is due to Warwicker and Watson (1982), which was followed by many others (e.g., Davis and McCammon (1990), Holst (1993), Davis et al (1991), Juffer et al (1991), Juffer (1998), Honig and Nicholls (1995), Bashford et al (1988), Bashford and Karplus (1990), Beroza et al (1991), Warwicker (1999), Baker et al (2001), Li et al (2005), and Anandakrishnan et al (2012)). This approach is indicated in Fig.…”

Investigation of protein binding affinity and preferred orientations in ion exchange systems using a homologous protein library

“…The pH value was equal to the pH value of buffer solution (pH 5). pK a values of the amino acid residues of each proteins in the library were obtained through the on-line PROPKA calculation (http://propka.chem.uiowa.edu/), in which the effects of desolvation, hydrogen bonding and intra-protein charge-charge interactions that cause variations in pK a values were considered (Li et al, 2005). The surface electrostatic potential (EP) function of the protein is also determined from the pH-sensitive charge assignment:…”

“…8a). An alternative explanation may be that the glutamate at position 50 in the native protein may have minimal negative charge, since the calculated pK a (Li et al, 2005) of this was close to pH 5 (pK a ¼ 4.6). As can be seen in Figure 8a, a large positive charge cluster exists at the top left region of the protein as shown.…”