PKAD: a database of experimentally measured pKa values of ionizable groups in proteins

Abstract Ionizable residues play key roles in many biological phenomena including protein folding, enzyme catalysis and binding. We present PKAD, a database of experimentally measured pKas of protein residues reported in the literature or taken from existing databases. The database contains pKa data for 1350 residues in 157 wild-type proteins and for 232 residues in 45 mutant proteins. Most of these values are for Asp, Glu, His and Lys amino acids. The database is available as downloadable file as well as a web server (http://compbio.clemson.edu/pkad). The PKAD database can be used as a benchmarking source for development and improvement of pKa’s prediction methods. The web server provides additional information taken from the corresponding structures and amino acid sequences, which allows for easy search and grouping of the experimental pKas according to various biophysical characteristics, amino acid type and others.

[1]  E. Lattman,et al.  Experimental measurement of the effective dielectric in the hydrophobic core of a protein. , 1997, Biophysical chemistry.

[2]  T. N. Bhat,et al.  The Protein Data Bank , 2000, Nucleic Acids Res..

[3]  R. L. Baldwin,et al.  The pKa of His-24 in the folding transition state of apomyoglobin , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[4]  C. Pace,et al.  A summary of the measured pK values of the ionizable groups in folded proteins , 2008, Protein science : a publication of the Protein Society.

[5]  G. Brayer,et al.  High-resolution three-dimensional structure of horse heart cytochrome c. , 1990, Journal of molecular biology.

[6]  A. Elcock.  Prediction of functionally important residues based solely on the computed energetics of protein structure. , 2001, Journal of molecular biology.

[7]  D. Bashford,et al.  Use of 1H NMR spectroscopy and computer simulations To analyze histidine pKa changes in a protein tyrosine phosphatase: experimental and theoretical determination of electrostatic properties in a small protein. , 1997, Biochemistry.

[8]  F. Gurd,et al.  pH-dependent processes in proteins. , 1985, CRC critical reviews in biochemistry.

[9]  B. García-Moreno E.,et al.  Structural interpretation of pH and salt-dependent processes in proteins with computational methods. , 2004, Methods in enzymology.

[10]  A. Warshel,et al.  What are the dielectric “constants” of proteins and how to validate electrostatic models? , 2001, Proteins.

[11]  T. Harris,et al.  Structural Basis of Perturbed pKa Values of Catalytic Groups in Enzyme Active Sites , 2002, IUBMB life.

[12]  D. E. Anderson,et al.  pH-induced denaturation of proteins: a single salt bridge contributes 3-5 kcal/mol to the free energy of folding of T4 lysozyme. , 1990, Biochemistry.

[13]  C. Pace,et al.  Buried, charged, non-ion-paired aspartic acid 76 contributes favorably to the conformational stability of ribonuclease T1. , 1999, Biochemistry.

[14]  S. Linse,et al.  Measurement and modelling of sequence-specific pKa values of lysine residues in calbindin D9k. , 1996, Journal of molecular biology.

[15]  J. Schlessman,et al.  Electrostatic effects in a network of polar and ionizable groups in staphylococcal nuclease. , 2008, Journal of molecular biology.

[16]  B. Kuhlman,et al.  pKa values and the pH dependent stability of the N-terminal domain of L9 as probes of electrostatic interactions in the denatured state. Differentiation between local and nonlocal interactions. , 1999, Biochemistry.

[17]  M. L. Tasayco,et al.  On the NMR analysis of pKa values in the unfolded state of proteins by extrapolation to zero denaturant. , 2007, Biophysical chemistry.

[18]  J. Nielsen,et al.  The pKa Cooperative: A collaborative effort to advance structure‐based calculations of pKa values and electrostatic effects in proteins , 2011, Proteins.

[19]  M. D. Joshi,et al.  Complete measurement of the pKa values of the carboxyl and imidazole groups in Bacillus circulans xylanase , 1997, Protein science : a publication of the Protein Society.

[20]  J. Nielsen.  Analyzing enzymatic pH activity profiles and protein titration curves using structure-based pKa calculations and titration curve fitting. , 2009, Methods in enzymology.

[21]  B. Honig,et al.  Classical electrostatics in biology and chemistry. , 1995, Science.

[22]  A. D. Robertson,et al.  Hydrogen bonds and the pH dependence of ovomucoid third domain stability. , 1995, Biochemistry.

[23]  M. D. Joshi,et al.  Dissecting the electrostatic interactions and pH-dependent activity of a family 11 glycosidase. , 2001, Biochemistry.

[24]  Emil Alexov,et al.  Protonation and pK changes in protein–ligand binding , 2013, Quarterly Reviews of Biophysics.

[25]  J. Markley.  Observation of histidine residues in proteins by nuclear magnetic resonance spectroscopy , 1975 .

[26]  M. Ondrechen,et al.  THEMATICS: A simple computational predictor of enzyme function from structure , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[27]  D. Raleigh,et al.  Analysis of the pH-dependent folding and stability of histidine point mutants allows characterization of the denatured state and transition state for protein folding. , 2005, Journal of molecular biology.

[28]  J. Nielsen,et al.  Titration_DB: Storage and analysis of NMR‐monitored protein pH titration curves , 2010, Proteins.

[29]  P. Frey,et al.  Mechanistic roles of tyrosine 149 and serine 124 in UDP-galactose 4-epimerase from Escherichia coli. , 1997, Biochemistry.

[30]  K. Sharp,et al.  On the calculation of pKas in proteins , 1993, Proteins.

[31]  Jan H. Jensen,et al.  Very fast empirical prediction and rationalization of protein pKa values , 2005, Proteins.

[32]  J. D. Reid,et al.  A classical enzyme active center motif lacks catalytic competence until modulated electrostatically. , 1997, Biochemistry.

[33]  G. Rose,et al.  Hydrophobicity of amino acid subgroups in proteins , 1990, Proteins.