Determination of the structure form of the fourth ligand of zinc in acutolysin a using combined quantum mechanical and molecular mechanical simulation

Emilia L. Wu, Kin Yiu Wong, Xin Zhang, Keli Han, Jiali Gao

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Acutolysin A, which is isolated from the snake venom of Agkistrodon acutus, is a member of the SVMPs subfamily of the metzincin family, and it is a snake venom zinc metalloproteinase possessing only one catalytic domain. The catalytic zinc ion, in the active site, is coordinated in a tetrahedral manner with three imidazole nitrogen atoms of histidine and one oxygen atom. It is uncertain whether this oxygen atom is a water molecule or a hydroxide ion just from the three-dimensional X-ray crystal structure. The identity of the fourth ligand of zinc is theoretically determined for the first time by performing both combined quantum mechanical and molecular mechanical (QM/MM) simulation and high-level quantum mechanical calculations. All of the results obtained indicate that the fourth ligand in the active site of the reported X-ray crystal structure is a water molecule rather than a hydroxide anion. On the basis of these theoretical results, we note that the experimental observed pH dependence of the proteolytic and hemorrhagic activity of Acutolysin A can be attributed to the deprotonation of the zinc-bound water to yield a better nucleophile, the hydroxide ion. Structural analyses revealed structural details useful for the understanding of acutolysin catalytic mechanism.

Original languageEnglish (US)
Pages (from-to)2477-2485
Number of pages9
JournalJournal of Physical Chemistry B
Volume113
Issue number8
DOIs
StatePublished - Feb 26 2009

Fingerprint

Zinc
zinc
Ligands
hydroxides
snakes
Snake Venoms
ligands
Atoms
Water
oxygen atoms
Ions
simulation
Crystal structure
water
Oxygen
X rays
Deprotonation
Nucleophiles
ions
crystal structure

All Science Journal Classification (ASJC) codes

  • Physical and Theoretical Chemistry
  • Surfaces, Coatings and Films
  • Materials Chemistry

Cite this

@article{0012b813dfb84d4b99ff070c4a517759,
title = "Determination of the structure form of the fourth ligand of zinc in acutolysin a using combined quantum mechanical and molecular mechanical simulation",
abstract = "Acutolysin A, which is isolated from the snake venom of Agkistrodon acutus, is a member of the SVMPs subfamily of the metzincin family, and it is a snake venom zinc metalloproteinase possessing only one catalytic domain. The catalytic zinc ion, in the active site, is coordinated in a tetrahedral manner with three imidazole nitrogen atoms of histidine and one oxygen atom. It is uncertain whether this oxygen atom is a water molecule or a hydroxide ion just from the three-dimensional X-ray crystal structure. The identity of the fourth ligand of zinc is theoretically determined for the first time by performing both combined quantum mechanical and molecular mechanical (QM/MM) simulation and high-level quantum mechanical calculations. All of the results obtained indicate that the fourth ligand in the active site of the reported X-ray crystal structure is a water molecule rather than a hydroxide anion. On the basis of these theoretical results, we note that the experimental observed pH dependence of the proteolytic and hemorrhagic activity of Acutolysin A can be attributed to the deprotonation of the zinc-bound water to yield a better nucleophile, the hydroxide ion. Structural analyses revealed structural details useful for the understanding of acutolysin catalytic mechanism.",
author = "Wu, {Emilia L.} and Wong, {Kin Yiu} and Xin Zhang and Keli Han and Jiali Gao",
year = "2009",
month = "2",
day = "26",
doi = "10.1021/jp808182y",
language = "English (US)",
volume = "113",
pages = "2477--2485",
journal = "Journal of Physical Chemistry B",
issn = "1520-6106",
number = "8",

}

Determination of the structure form of the fourth ligand of zinc in acutolysin a using combined quantum mechanical and molecular mechanical simulation. / Wu, Emilia L.; Wong, Kin Yiu; Zhang, Xin; Han, Keli; Gao, Jiali.

In: Journal of Physical Chemistry B, Vol. 113, No. 8, 26.02.2009, p. 2477-2485.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Determination of the structure form of the fourth ligand of zinc in acutolysin a using combined quantum mechanical and molecular mechanical simulation

AU - Wu, Emilia L.

AU - Wong, Kin Yiu

AU - Zhang, Xin

AU - Han, Keli

AU - Gao, Jiali

PY - 2009/2/26

Y1 - 2009/2/26

N2 - Acutolysin A, which is isolated from the snake venom of Agkistrodon acutus, is a member of the SVMPs subfamily of the metzincin family, and it is a snake venom zinc metalloproteinase possessing only one catalytic domain. The catalytic zinc ion, in the active site, is coordinated in a tetrahedral manner with three imidazole nitrogen atoms of histidine and one oxygen atom. It is uncertain whether this oxygen atom is a water molecule or a hydroxide ion just from the three-dimensional X-ray crystal structure. The identity of the fourth ligand of zinc is theoretically determined for the first time by performing both combined quantum mechanical and molecular mechanical (QM/MM) simulation and high-level quantum mechanical calculations. All of the results obtained indicate that the fourth ligand in the active site of the reported X-ray crystal structure is a water molecule rather than a hydroxide anion. On the basis of these theoretical results, we note that the experimental observed pH dependence of the proteolytic and hemorrhagic activity of Acutolysin A can be attributed to the deprotonation of the zinc-bound water to yield a better nucleophile, the hydroxide ion. Structural analyses revealed structural details useful for the understanding of acutolysin catalytic mechanism.

AB - Acutolysin A, which is isolated from the snake venom of Agkistrodon acutus, is a member of the SVMPs subfamily of the metzincin family, and it is a snake venom zinc metalloproteinase possessing only one catalytic domain. The catalytic zinc ion, in the active site, is coordinated in a tetrahedral manner with three imidazole nitrogen atoms of histidine and one oxygen atom. It is uncertain whether this oxygen atom is a water molecule or a hydroxide ion just from the three-dimensional X-ray crystal structure. The identity of the fourth ligand of zinc is theoretically determined for the first time by performing both combined quantum mechanical and molecular mechanical (QM/MM) simulation and high-level quantum mechanical calculations. All of the results obtained indicate that the fourth ligand in the active site of the reported X-ray crystal structure is a water molecule rather than a hydroxide anion. On the basis of these theoretical results, we note that the experimental observed pH dependence of the proteolytic and hemorrhagic activity of Acutolysin A can be attributed to the deprotonation of the zinc-bound water to yield a better nucleophile, the hydroxide ion. Structural analyses revealed structural details useful for the understanding of acutolysin catalytic mechanism.

UR - http://www.scopus.com/inward/record.url?scp=65249134433&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=65249134433&partnerID=8YFLogxK

U2 - 10.1021/jp808182y

DO - 10.1021/jp808182y

M3 - Article

C2 - 19191509

AN - SCOPUS:65249134433

VL - 113

SP - 2477

EP - 2485

JO - Journal of Physical Chemistry B

JF - Journal of Physical Chemistry B

SN - 1520-6106

IS - 8

ER -