| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Biophys J, October 2002, p. 1731-1748, Vol. 83, No. 4
Department of Physics, City College of New York, New York 10031 USA
Protein stability and function relies on residues being
in their appropriate ionization states at physiological pH. In situ residue pKas also provides a sensitive measure of the local
protein environment. Multiconformation continuum electrostatics (MCCE) combines continuum electrostatics and molecular mechanics force fields
in Monte Carlo sampling to simultaneously calculate side chain
ionization and conformation. The response of protein to charges is
incorporated both in the protein dielectric constant (
prot) of four and by explicit conformational changes.
The pKa of 166 residues in 12 proteins was determined. The
root mean square error is 0.83 pH units, and >90% have errors of <1
pH units whereas only 3% have errors >2 pH units. Similar results are
found with crystal and solution structures, showing that the method's
explicit conformational sampling reduces sensitivity to the initial
structure. The outcome also changes little with protein dielectric
constant (prot 4-20). Multiconformation continuum
electrostatics titrations show coupling of conformational flexibility
and changes in ionization state. Examples are provided where ionizable
side chain position (protein G), Asn orientation (lysozyme), His
tautomer distribution (RNase A), and phosphate ion binding (RNase A and
H) change with pH. Disallowing these motions changes the calculated
pKa.
Biophys J, October 2002, p. 1731-1748, Vol. 83, No. 4
© 2002 by the Biophysical Society 0006-3495/02/10/1731/18 $2.00
This article has been cited by other articles:
 |
|
 |
|
  M. J. Harms, J. L. Schlessman, M. S. Chimenti, G. R. Sue, A. Damjanovic, and B. Garcia-Moreno E. A buried lysine that titrates with a normal pKa : Role of conformational flexibility at the protein-water interface as a determinant of pKa values Protein Sci., May 1, 2008; 17(5): 833 - 845. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Andersson, K. Hauser, E.-L. Karjalainen, and A. Barth Protonation and Hydrogen Bonding of Ca2+ Site Residues in the E2P Phosphoenzyme Intermediate of Sarcoplasmic Reticulum Ca2+-ATPase Studied by a Combination of Infrared Spectroscopy and Electrostatic Calculations Biophys. J., January 15, 2008; 94(2): 600 - 611. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Brock, K. Talley, K. Coley, P. Kundrotas, and E. Alexov Optimization of Electrostatic Interactions in Protein-Protein Complexes Biophys. J., November 15, 2007; 93(10): 3340 - 3352. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Hauser and A. Barth Side-Chain Protonation and Mobility in the Sarcoplasmic Reticulum Ca2+-ATPase: Implications for Proton Countertransport and Ca2+ Release Biophys. J., November 1, 2007; 93(9): 3259 - 3270. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. A. Karp, A. G. Gittis, M. R. Stahley, C. A. Fitch, W. E. Stites, and B. Garcia-Moreno E. High Apparent Dielectric Constant Inside a Protein Reflects Structural Reorganization Coupled to the Ionization of an Internal Asp Biophys. J., March 15, 2007; 92(6): 2041 - 2053. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Machuqueiro and A. M. Baptista The pH-Dependent Conformational States of Kyotorphin: A Constant-pH Molecular Dynamics Study Biophys. J., March 15, 2007; 92(6): 1836 - 1845. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Bertonati, B. Honig, and E. Alexov Poisson-Boltzmann Calculations of Nonspecific Salt Effects on Protein-Protein Binding Free Energies Biophys. J., March 15, 2007; 92(6): 1891 - 1899. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. J. Kundrotas and E. Alexov Electrostatic Properties of Protein-Protein Complexes Biophys. J., September 1, 2006; 91(5): 1724 - 1736. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. T. Suydam, C. D. Snow, V. S. Pande, and S. G. Boxer Electric fields at the active site of an enzyme: direct comparison of experiment with theory. Science, July 14, 2006; 313(5784): 200 - 204. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. A. Kantardjiev and B. P. Atanasov PHEPS: web-based pH-dependent Protein Electrostatics Server. Nucleic Acids Res., July 1, 2006; 34(Web Server issue): W43 - W47. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Ma, X. Zhao, A. N. Eddine, A. Geerlof, X. Li, J. E. Cronan, S. H. E. Kaufmann, and M. Wilmanns The Mycobacterium tuberculosis LipB enzyme functions as a cysteine/lysine dyad acyltransferase PNAS, June 6, 2006; 103(23): 8662 - 8667. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. L. Thurlkill, G. R. Grimsley, J. M. Scholtz, and C. N. Pace pK values of the ionizable groups of proteins Protein Sci., May 1, 2006; 15(5): 1214 - 1218. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Olkhova, C. Hunte, E. Screpanti, E. Padan, and H. Michel Multiconformation continuum electrostatics analysis of the NhaA Na+/H+ antiporter of Escherichia coli with functional implications PNAS, February 21, 2006; 103(8): 2629 - 2634. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. P. Toseland, H. McSparron, M. N. Davies, and D. R. Flower PPD v1.0--an integrated, web-accessible database of experimentally determined protein pKa values Nucleic Acids Res., January 1, 2006; 34(suppl_1): D199 - D203. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. C. Gordon, J. B. Myers, T. Folta, V. Shoja, L. S. Heath, and A. Onufriev H++: a server for estimating pKas and adding missing hydrogens to macromolecules Nucleic Acids Res., July 1, 2005; 33(suppl_2): W368 - W371. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Miteva, P. Tuffery, and B. O. Villoutreix PCE: web tools to compute protein continuum electrostatics Nucleic Acids Res., July 1, 2005; 33(suppl_2): W372 - W375. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Khandogin and C. L. Brooks III Constant pH Molecular Dynamics with Proton Tautomerism Biophys. J., July 1, 2005; 89(1): 141 - 157. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Archontis and T. Simonson Proton Binding to Proteins: A Free-Energy Component Analysis Using a Dielectric Continuum Model Biophys. J., June 1, 2005; 88(6): 3888 - 3904. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. H. Haas and C. R. D. Lancaster Calculated Coupling of Transmembrane Electron and Proton Transfer in Dihemic Quinol:Fumarate Reductase Biophys. J., December 1, 2004; 87(6): 4298 - 4315. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. S. Petrov, G. Lamm, and G. R. Pack The Triplex-Hairpin Transition in Cytosine-Rich DNA Biophys. J., December 1, 2004; 87(6): 3954 - 3973. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Warwicker Improved pKa calculations through flexibility based sampling of a water-dominated interaction scheme Protein Sci., October 22, 2004; 13(10): 2793 - 2805. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Oren, S. J. Fleishman, A. Kessel, and N. Ben-Tal Free Diffusion of Steroid Hormones Across Biomembranes: A Simplex Search with Implicit Solvent Model Calculations Biophys. J., August 1, 2004; 87(2): 768 - 779. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Varma and E. Jakobsson Ionization States of Residues in OmpF and Mutants: Effects of Dielectric Constant and Interactions between Residues Biophys. J., February 1, 2004; 86(2): 690 - 704. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Dong, M. Vijayakumar, and H.-X. Zhou Comparison of Calculation and Experiment Implicates Significant Electrostatic Contributions to the Binding Stability of Barnase and Barstar Biophys. J., July 1, 2003; 85(1): 49 - 60. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
