Accounting for ligand-bound metal ions in docking small molecules on adenylyl cyclase toxins

Deliang Chen, Gerd Menche, Trevor D. Power, Laurie Sower, Johnny Peterson, Catherine H. Schein

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

The adenylyl cyclase toxins produced by bacteria (such as the edema factor (EF) of Bacillus anthracis and CyaA of Bordetella pertussis) are important virulence factors in anthrax and whooping cough. Co-crystal structures of these proteins differ in the number and positioning of metal ions in the active site. Metal ions bound only to the ligands in the crystal structures are not included during the docking. To determine what effect these "missing" metals have on docking results, the AutoDock, LigandFit/Cerius2, and FlexX programs were compared for their ability to correctly place substrate analogues and inhibitors into the active sites of the crystal structures of EF, CyaA, and mammalian adenylate cyclase. Protonating the phosphates of substrate analogues improved the accuracy of docking into the active site of CyaA, where the grid did not account for one of the three Mg2+ ions in the crystal structure. The AutoDock ranking (based on docking energies) of a test group of compounds was relatively unaffected by protonation of carboxyl groups. However, the ranking by FlexX-ChemScore varied significantly, especially for docking to CyaA, suggesting that alternate protonation states should be tested when screening compound libraries with this program. When the charges on the bound metal were set correctly, AutoDock was the most reliable program of the three tested with respect to positioning substrate analogues and ranking compounds according to their experimentally determined ability to inhibit EF.

Original languageEnglish (US)
Pages (from-to)593-605
Number of pages13
JournalProteins: Structure, Function and Genetics
Volume67
Issue number3
DOIs
StatePublished - May 15 2007

Fingerprint

Adenylyl Cyclases
Metal ions
Crystal structure
Metals
Ions
Ligands
Catalytic Domain
Molecules
Protonation
Substrates
Bordetella pertussis
Anthrax
Whooping Cough
Virulence Factors
Libraries
Bacteria
Screening
Phosphates
Proteins
edema factor

Keywords

  • AutoDock
  • Bacillus anthracis
  • Bordetella pertussis
  • CyaA
  • Edema factor
  • FlexX
  • Ligand protonation
  • Metal ion binding to proteins and nucleotides

ASJC Scopus subject areas

  • Genetics
  • Structural Biology
  • Biochemistry

Cite this

Accounting for ligand-bound metal ions in docking small molecules on adenylyl cyclase toxins. / Chen, Deliang; Menche, Gerd; Power, Trevor D.; Sower, Laurie; Peterson, Johnny; Schein, Catherine H.

In: Proteins: Structure, Function and Genetics, Vol. 67, No. 3, 15.05.2007, p. 593-605.

Research output: Contribution to journalArticle

Chen, Deliang ; Menche, Gerd ; Power, Trevor D. ; Sower, Laurie ; Peterson, Johnny ; Schein, Catherine H. / Accounting for ligand-bound metal ions in docking small molecules on adenylyl cyclase toxins. In: Proteins: Structure, Function and Genetics. 2007 ; Vol. 67, No. 3. pp. 593-605.
@article{0d9d30a86931471fba687c07b87b169e,
title = "Accounting for ligand-bound metal ions in docking small molecules on adenylyl cyclase toxins",
abstract = "The adenylyl cyclase toxins produced by bacteria (such as the edema factor (EF) of Bacillus anthracis and CyaA of Bordetella pertussis) are important virulence factors in anthrax and whooping cough. Co-crystal structures of these proteins differ in the number and positioning of metal ions in the active site. Metal ions bound only to the ligands in the crystal structures are not included during the docking. To determine what effect these {"}missing{"} metals have on docking results, the AutoDock, LigandFit/Cerius2, and FlexX programs were compared for their ability to correctly place substrate analogues and inhibitors into the active sites of the crystal structures of EF, CyaA, and mammalian adenylate cyclase. Protonating the phosphates of substrate analogues improved the accuracy of docking into the active site of CyaA, where the grid did not account for one of the three Mg2+ ions in the crystal structure. The AutoDock ranking (based on docking energies) of a test group of compounds was relatively unaffected by protonation of carboxyl groups. However, the ranking by FlexX-ChemScore varied significantly, especially for docking to CyaA, suggesting that alternate protonation states should be tested when screening compound libraries with this program. When the charges on the bound metal were set correctly, AutoDock was the most reliable program of the three tested with respect to positioning substrate analogues and ranking compounds according to their experimentally determined ability to inhibit EF.",
keywords = "AutoDock, Bacillus anthracis, Bordetella pertussis, CyaA, Edema factor, FlexX, Ligand protonation, Metal ion binding to proteins and nucleotides",
author = "Deliang Chen and Gerd Menche and Power, {Trevor D.} and Laurie Sower and Johnny Peterson and Schein, {Catherine H.}",
year = "2007",
month = "5",
day = "15",
doi = "10.1002/prot.21249",
language = "English (US)",
volume = "67",
pages = "593--605",
journal = "Proteins: Structure, Function and Bioinformatics",
issn = "0887-3585",
publisher = "Wiley-Liss Inc.",
number = "3",

}

TY - JOUR

T1 - Accounting for ligand-bound metal ions in docking small molecules on adenylyl cyclase toxins

AU - Chen, Deliang

AU - Menche, Gerd

AU - Power, Trevor D.

AU - Sower, Laurie

AU - Peterson, Johnny

AU - Schein, Catherine H.

PY - 2007/5/15

Y1 - 2007/5/15

N2 - The adenylyl cyclase toxins produced by bacteria (such as the edema factor (EF) of Bacillus anthracis and CyaA of Bordetella pertussis) are important virulence factors in anthrax and whooping cough. Co-crystal structures of these proteins differ in the number and positioning of metal ions in the active site. Metal ions bound only to the ligands in the crystal structures are not included during the docking. To determine what effect these "missing" metals have on docking results, the AutoDock, LigandFit/Cerius2, and FlexX programs were compared for their ability to correctly place substrate analogues and inhibitors into the active sites of the crystal structures of EF, CyaA, and mammalian adenylate cyclase. Protonating the phosphates of substrate analogues improved the accuracy of docking into the active site of CyaA, where the grid did not account for one of the three Mg2+ ions in the crystal structure. The AutoDock ranking (based on docking energies) of a test group of compounds was relatively unaffected by protonation of carboxyl groups. However, the ranking by FlexX-ChemScore varied significantly, especially for docking to CyaA, suggesting that alternate protonation states should be tested when screening compound libraries with this program. When the charges on the bound metal were set correctly, AutoDock was the most reliable program of the three tested with respect to positioning substrate analogues and ranking compounds according to their experimentally determined ability to inhibit EF.

AB - The adenylyl cyclase toxins produced by bacteria (such as the edema factor (EF) of Bacillus anthracis and CyaA of Bordetella pertussis) are important virulence factors in anthrax and whooping cough. Co-crystal structures of these proteins differ in the number and positioning of metal ions in the active site. Metal ions bound only to the ligands in the crystal structures are not included during the docking. To determine what effect these "missing" metals have on docking results, the AutoDock, LigandFit/Cerius2, and FlexX programs were compared for their ability to correctly place substrate analogues and inhibitors into the active sites of the crystal structures of EF, CyaA, and mammalian adenylate cyclase. Protonating the phosphates of substrate analogues improved the accuracy of docking into the active site of CyaA, where the grid did not account for one of the three Mg2+ ions in the crystal structure. The AutoDock ranking (based on docking energies) of a test group of compounds was relatively unaffected by protonation of carboxyl groups. However, the ranking by FlexX-ChemScore varied significantly, especially for docking to CyaA, suggesting that alternate protonation states should be tested when screening compound libraries with this program. When the charges on the bound metal were set correctly, AutoDock was the most reliable program of the three tested with respect to positioning substrate analogues and ranking compounds according to their experimentally determined ability to inhibit EF.

KW - AutoDock

KW - Bacillus anthracis

KW - Bordetella pertussis

KW - CyaA

KW - Edema factor

KW - FlexX

KW - Ligand protonation

KW - Metal ion binding to proteins and nucleotides

UR - http://www.scopus.com/inward/record.url?scp=34247251854&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34247251854&partnerID=8YFLogxK

U2 - 10.1002/prot.21249

DO - 10.1002/prot.21249

M3 - Article

VL - 67

SP - 593

EP - 605

JO - Proteins: Structure, Function and Bioinformatics

JF - Proteins: Structure, Function and Bioinformatics

SN - 0887-3585

IS - 3

ER -