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Very Fast Prediction And Rationalization Of PKa Values For Protein–ligand Complexes

Delphine Bas, D. Rogers, Jan H. Jensen
Published 2008 · Chemistry, Medicine

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The PROPKA method for the prediction of the pKa values of ionizable residues in proteins is extended to include the effect of non‐proteinaceous ligands on protein pKa values as well as predict the change in pKa values of ionizable groups on the ligand itself. This new version of PROPKA (PROPKA 2.0) is, as much as possible, developed by adapting the empirical rules underlying PROPKA 1.0 to ligand functional groups. Thus, the speed of PROPKA is retained, so that the pKa values of all ionizable groups are computed in a matter of seconds for most proteins. This adaptation is validated by comparing PROPKA 2.0 predictions to experimental data for 26 protein–ligand complexes including trypsin, thrombin, three pepsins, HIV‐1 protease, chymotrypsin, xylanase, hydroxynitrile lyase, and dihydrofolate reductase. For trypsin and thrombin, large protonation state changes (|n| > 0.5) have been observed experimentally for 4 out of 14 ligand complexes. PROPKA 2.0 and Klebe's PEOE approach (Czodrowski P et al. J Mol Biol 2007;367:1347–1356) both identify three of the four large protonation state changes. The protonation state changes due to plasmepsin II, cathepsin D and endothiapepsin binding to pepstatin are predicted to within 0.4 proton units at pH 6.5 and 7.0, respectively. The PROPKA 2.0 results indicate that structural changes due to ligand binding contribute significantly to the proton uptake/release, as do residues far away from the binding site, primarily due to the change in the local environment of a particular residue and hence the change in the local hydrogen bonding network. Overall the results suggest that PROPKA 2.0 provides a good description of the protein–ligand interactions that have an important effect on the pKa values of titratable groups, thereby permitting fast and accurate determination of the protonation states of key residues and ligand functional groups within the binding or active site of a protein. Proteins 2008. © 2008 Wiley‐Liss, Inc.
This paper references
An empirical model for electrostatic interactions in proteins incorporating multiple geometry‐dependent dielectric constants
M. Wisz (2003)
Structure and inhibition of plasmepsin II, a hemoglobin-degrading enzyme from Plasmodium falciparum.
A. Silva (1996)
Hydrogen bonding and catalysis: a novel explanation for how a single amino acid substitution can change the pH optimum of a glycosidase.
M. D. Joshi (2000)
Development, validation, and application of adapted PEOE charges to estimate pKa values of functional groups in protein–ligand complexes
P. Czodrowski (2006)
Three‐dimensional structures of enzyme‐substrate complexes of the hydroxynitrile lyase from hevea brasiliensis
J. Zuegg (1999)
The determinants of pK(a)s in proteins
J. Antosiewicz (1996)
Very fast empirical prediction and rationalization of protein pKa values
H. Li (2005)
van der Waals Volumes and Radii
A. Bondi (1964)
Intrinsic pKas of ionizable residues in proteins: An explicit solvent calculation for lysozyme
G. S. Del Buono (1994)
Matwiyoff NA, Blakley RL. C-13 nuclear magnetic-resonance study of protonation of methotrexate and aminopterin bound to dihydrofolatereductase
L Cocco (1981)
The Protein Data Bank
H. Berman (2000)
pK a of Protein-Ligand Complexes
Redesigning protein p K ( a ) values
GS DelBuono (2007)
Prediction of pH-dependent properties of proteins.
J. Antosiewicz (1994)
Ionization states of the catalytic residues in HIV-1 protease
R. Smith (1996)
Dissecting the electrostatic interactions and pH-dependent activity of a family 11 glycosidase.
M. D. Joshi (2001)
Electrostatic basis of structure-function correlation in proteins
A. Warshel (1981)
Redesigning protein pK(a) values. Protein Sci 2007;16:239–249
BM Tynan-Connolly (2007)
A self-consistent, microenvironment modulated screened coulomb potential approximation to calculate pH-dependent electrostatic effects in proteins.
E. Mehler (1999)
of HIV - 1 protease with KNI - 272 , a tight - binding transition - state analog containing allophenyl - norstatine
Lam PYS (1995)
Improving the Continuum Dielectric Approach to Calculating pKas of Ionizable Groups in Proteins
E. Demchuk (1996)
Sugar ring distortion in the glycosyl-enzyme intermediate of a family G/11 xylanase.
G. Sidhu (1999)
A simple algorithm for the calculation of multiple site titration curves.
A. Karshikoff (1995)
Interpreting trends in the binding of cyclic ureas to HIV-1 protease.
K. Mardis (2001)
Conserved folding in retroviral proteases: crystal structure of a synthetic HIV-1 protease.
A. Wlodawer (1989)
Consideration of the pH-dependent inhibition of dihydrofolate reductase by methotrexate.
W. R. Cannon (1997)
The active site of aspartic proteinases
L. Pearl (1984)
Accurate Calculation of Hydration Free Energies Using Macroscopic Solvent Models
D. Sitkoff (1994)
NMR and X-ray Evidence That the HIV Protease Catalytic Aspartyl Groups Are Protonated in the Complex Formed by the Protease and a Non-Peptide Cyclic Urea-Based Inhibitor
T. Yamazaki (1994)
Toward the accurate first-principles prediction of ionization equilibria in proteins.
Jana Khandogin (2006)
Calculating pKa values in enzyme active sites
J. E. Nielsen (2003)
Crystal structures of Escherichia coli and Lactobacillus casei dihydrofolate reductase refined at 1.7 A resolution. I. General features and binding of methotrexate.
J. Bolin (1982)
Nuclear magnetic resonance study of the state of protonation of inhibitors bound to mutant dihydrofolate reductase lacking the active-site carboxyl.
R. London (1986)
Thermodynamic dissection of the binding energetics of KNI‐272, a potent HIV‐1 protease inhibitor
A. Velázquez-Campoy (2000)
Benchmarking pKa prediction
M. Davies (2005)
Analysing the pH-dependent properties of proteins using pKa calculations.
J. E. Nielsen (2007)
Empirical parametrization of pK values for carboxylic acids in proteins using a genetic algorithm.
Raquel Godoy-Ruiz (2005)
Protonation changes upon ligand binding to trypsin and thrombin: structural interpretation based on pK(a) calculations and ITC experiments.
P. Czodrowski (2007)
Redesigning protein pKa values
Barbara M. Tynan-Connolly (2007)
Development, validation, and application of adapted PEOE charges to estimate pK(a) values of functional groups in protein–ligand complexes
P Czodrowski (2006)
Electrostatic models for computing protonation and redox equilibria in proteins
G. Ullmann (1999)
Waals volumes 1 radii
Bondi A. Van der (1964)
Protonated state of methotrexate, trimethoprim, and pyrimethamine bound to dihydrofolate reductase.
L. Cocco (1983)
The pH-dependence of the binding of dihydrofolate and substrate analogues to dihydrofolate reductase from Escherichia coli.
S. R. Stone (1983)
Cyclic HIV protease inhibitors: synthesis, conformational analysis, P2/P2' structure-activity relationship, and molecular recognition of cyclic ureas.
P. Lam (1996)
Crystal structures of native and inhibited forms of human cathepsin D: implications for lysosomal targeting and drug design.
E. Baldwin (1993)
Factorising ligand affinity: a combined thermodynamic and crystallographic study of trypsin and thrombin inhibition.
F. Dullweber (2001)
The three-dimensional structure of the aspartyl protease from the HIV-1 isolate BRU.
S. Spinelli (1991)
On the Calculation of p K ( a ) S in proteins
JJ Havranek (1993)
Conformational switching in an aspartic proteinase
A. Y. Lee (1998)
Atypical Protonation States in the Active Site of HIV-1 Protease: A Computational Study
P. Czodrowski (2007)
CHARMM: A program for macromolecular energy, minimization, and dynamics calculations
Bernard R. Brooks (1983)
Computer Simulation Studies of the Catalytic Mechanism of Human Aldose Reductase
Péter Várnai† and (2000)
Accurate, conformation-dependent predictions of solvent effects on protein ionization constants
P. Barth (2007)
C-13 nuclear magnetic-resonance study of protonation of methotrexate and aminopterin bound to dihydrofolatereductase
L Cocco (1981)
Observation of a Short, Strong Hydrogen Bond in the Active Site of Hydroxynitrile Lyase from Hevea brasiliensis Explains a Large pKa Shift of the Catalytic Base Induced by the Reaction Intermediate*
G. Stranzl (2004)
pKa's of ionizable groups in proteins: atomic detail from a continuum electrostatic model.
D. Bashford (1990)
A statistical approach to the prediction of pKa values in proteins
Y. He (2007)
Dissection of the pH dependence of inhibitor binding energetics for an aspartic protease: direct measurement of the protonation states of the catalytic aspartic acid residues.
D. Xie (1997)
Thermodynamic mapping of the inhibitor site of the aspartic protease endothiapepsin.
J. Gomez (1995)
Crystal structure of the novel aspartic proteinase zymogen proplasmepsin
NK Bernstein (1999)
The Blue Obelisk—Interoperability in Chemical Informatics
R. Guha (2006)
A simple algorithm for the calculation of multiplesite titration curves. Protein Eng 1995;8:243–248
A. Karshikoff (1995)
Computing ionization states of proteins with a detailed charge model
J. Antosiewicz (1996)
Free energy of charges in solvated proteins: microscopic calculations using a reversible charging process.
A. Warshel (1986)
The OPLS [optimized potentials for liquid simulations] potential functions for proteins, energy minimizations for crystals of cyclic peptides and crambin.
W. Jorgensen (1988)
Carbon-13 nuclear magnetic resonance study of protonation of methotrexate and aminopterin bound to dihydrofolate reductase.
L. Cocco (1981)
Crystal structure of the novel aspartic proteinase zymogen proplasmepsin II from Plasmodium falciparum
N. K. Bernstein (1999)
Calculating proton uptake/release and binding free energy taking into account ionization and conformation changes induced by protein–inhibitor association: Application to plasmepsin, cathepsin D and endothiapepsin–pepstatin complexes
E. Alexov (2004)
Simulations of ion current in realistic models of ion channels: The KcsA potassium channel
A. Burykin (2002)
A simple protocol to estimate differences in protein binding affinity for enantiomers without prior resolution of racemates.
J. Fokkens (2006)
Conformational change of the methionine 20 loop of Escherichia coli dihydrofolate reductase modulates pKa of the bound dihydrofolate
Ilja V. Khavrutskii (2007)
Protein–protein binding is often associated with changes in protonation state
A. C. Mason (2008)
A new concept for the mechanism of action of chymotrypsin: the role of the low-barrier hydrogen bond.
C. S. Cassidy (1997)
On the calculation of pKas in proteins
A. Yang (1993)
Thermodynamic linkage between the binding of protons and inhibitors to HIV‐1 protease
J. Trylska (1999)
Structure of chymotrypsin-trifluoromethyl ketone inhibitor complexes: comparison of slowly and rapidly equilibrating inhibitors.
K. Brady (1990)
Proton binding to proteins: pK(a) calculations with explicit and implicit solvent models.
T. Simonson (2004)
Structure of HIV-1 protease with KNI-272, a tight-binding transition-state analog containing allophenylnorstatine.
E. Baldwin (1995)
The Open Babel Package, version 2
Van der Waals volumes 1 radii
A Bondi (1964)
On the Calculation of pK(a)S in proteins. Proteins 1993;15:252–265
AS Yang (1993)
Tanford-Kirkwood electrostatics for protein modeling.
J. Havranek (1999)
Optimizing the hydrogen‐bond network in Poisson–Boltzmann equation‐based pKa calculations
J. E. Nielsen (2001)
How dihydrofolate reductase facilitates protonation of dihydrofolate.
T. H. Rod (2003)
The determinants of pKas in proteins.
J. Antosiewicz (1996)
Crystallographic analysis of a complex between human immunodeficiency virus type 1 protease and acetyl-pepstatin at 2.0-A resolution.
P. Fitzgerald (1990)
Consistent Calculations of pKa's of Ionizable Residues in Proteins: Semi-microscopic and Microscopic Approaches
Y. Sham (1997)
The low barrier hydrogen bond (LBHB) proposal revisited: The case of the Asp ··· His pair in serine proteases
C. N. Schutz (2004)
Structure of chymotrypsin-trifluoromethyl ketone inhibitor complexes: comparison of slowly and rapidly equilibrating inhibitors.
K. Brady (1990)
The OPLS potential functions for proteins
W. Jorgensen (1988)

This paper is referenced by
A Simple PB/LIE Free Energy Function Accurately Predicts the Peptide Binding Specificity of the Tiam1 PDZ Domain
N. Panel (2017)
Exploration of structural and physicochemical properties of small molecules to inhibit NMDA functionality
T. Hossain (2018)
For Review. Confidential - ACS
M. Gidley (2009)
Computational approaches to identifying and characterizing protein binding sites for ligand design
S. Henrich (2010)
Investigation of Indazole Unbinding Pathways in CYP2E1 by Molecular Dynamics Simulations
Zhonghua Shen (2012)
Multi-Target Chemometric Modelling, Fragment Analysis and Virtual Screening with ERK Inhibitors as Potential Anticancer Agents
A. K. Halder (2019)
Molecular Docking Based on Virtual Screening, Molecular Dynamics and Atoms in Molecules Studies to Identify the Potential Human Epidermal Receptor 2 Intracellular Domain Inhibitors
B. Ghalami-Choobar (2018)
S 1 Supporting information for : Pd ( II ) and Ni ( II ) complexes featuring a “ phosphasalen ” ligand : synthesis and DFT study
M. J. Frisch (2011)
Substrate-Assisted and Enzymatic Pretransfer Editing of Nonstandard Amino Acids by Methionyl-tRNA Synthetase.
Grant B Fortowsky (2015)
Origin of Enzymatic Kinetic Isotope Effects in Human Purine Nucleoside Phosphorylase
M. Roca (2017)
Structural insights into the loss of catalytic competence in pectate lyase activity at low pH
S. Ali (2015)
Estimation of the Binding Free Energy of AC1NX476 to HIV‐1 Protease Wild Type and Mutations Using Free Energy Perturbation Method
Son Tung Ngo (2015)
Hydrodynamic Steering in Protein Association Revisited: Surprisingly Minuscule Effects of Considerable Torques.
J. Antosiewicz (2017)
Biomolecular structure manipulation using tailored electromagnetic radiation: a proof of concept on a simplified model of the active site of bacterial DNA topoisomerase.
Daungruthai Jarukanont (2014)
Statistical Analysis and Prediction of Covalent Ligand Targeted Cysteine Residues.
W. Zhang (2017)
Biochemical Regulatory Features of Activation-Induced Cytidine Deaminase Remain Conserved from Lampreys to Humans
Emma M Quinlan (2017)
Validation of approximate nonempirical scoring model for menin-mixed lineage leukemia inhibitors
Wiktoria Jedwabny (2018)
Use of Broken-Symmetry Density Functional Theory To Characterize the IspH Oxidized State: Implications for IspH Mechanism and Inhibition
Patrick G. Blachly (2014)
New insights into the nature of observable reaction intermediates in cytochrome P450 NO reductase by using a combination of spectroscopy and quantum mechanics/molecular mechanics calculations.
Christoph Riplinger (2014)
Benchmarking Quantum Mechanics/Molecular Mechanics (QM/MM) Methods on the Thymidylate Synthase-Catalyzed Hydride Transfer.
K. Świderek (2017)
Atomistic molecular dynamics simulations of typical and atypical antipsychotic drugs at the dopamine D2 receptor (D2R) elucidates their inhibition mechanism
R. E. Salmas (2017)
Protonation States of the Catalytic Dyad of β-Secretase (BACE1) in the Presence of Chemically Diverse Inhibitors: A Molecular Docking Study
Arghya Barman (2012)
Anticancer properties of N-alkyl-2, 4-diphenylimidazo [1, 2-a] quinoxalin-1-amine derivatives; kinase inhibitors.
Z. Rezaei (2019)
Ion Pathways in the Sarcoplasmic Reticulum
Maike Bublitz (2013)
Binding modes and conformational changes of FK506-binding protein 51 induced by inhibitor bindings: insight into molecular mechanisms based on multiple simulation technologies
Jianzhong Chen (2019)
Pyridoxal 5'-phosphate dependent reactions: Analyzing the mechanism of aspartate aminotransferase.
T. Mueser (2020)
Uridine diphosphate release mechanism in O-N-acetylglucosamine (O-GlcNAc) transferase catalysis.
Nai She (2019)
Double anchorage to the membrane and intact inter‐chain disulfide bond are required for the low pH induced entry of tetanus and botulinum neurotoxins into neurons
M. Pirazzini (2011)
Identification of triazinoindol-benzimidazolones as nanomolar inhibitors of the Mycobacterium tuberculosis enzyme TDP-6-deoxy-d-xylo-4-hexopyranosid-4-ulose 3,5-epimerase (RmlC).
Sharmila Sivendran (2010)
1-(3-Deoxy-3-fluoro-beta-d-glucopyranosyl) pyrimidine derivatives as inhibitors of glycogen phosphorylase b: Kinetic, crystallographic and modelling studies.
Vicky G. Tsirkone (2010)
Dynamics of glucosamine-6-phosphate synthase catalysis.
S. Mouilleron (2011)
Role of the C-terminal domain of PCSK9 in degradation of the LDL receptors[S]
Ø. L. Holla (2011)
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