Insights into the structure and dynamics of the dinuclear zinc β-lactamase site from Bacteroides fragilis

Dimas Suárez, Edward Brothers, Kenneth M. Merz

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

Herein, we report quantum chemical calculations and molecular dynamics (MD) simulations of the dinuclear form of the Bacteroides fragilis zinc β-lactamase. We studied four different configurations which differ in the protonation state of the Asp103 residue and in the presence or absence of a Zn1-OH-Zn2 bridge. The flexibility of the Zn1-OH-Zn2 bridge was studied by means of quantum mechanical (QM) calculations on cluster models while the relative stabilities of the different configurations were estimated from QM linear scaling calculations on the enzyme. Contacts between important residues (Cys 104, Asp69, Lys185, etc.), the solvation of the zinc ions, and the conformation of the active site β-hairpin loop were characterized by the MD analyses. The influence of the buried sodium ion close to the Zn2 position was investigated by carrying out a secondary simulation where the sodium ion was replaced with an internal water molecule. The comparative structural analyses among the different MD trajectories augmented with energetic calculations have demonstrated that the B. fragilis protein efficiently binds the internal Na+ ion observed crystallographically. Moreover, we found that when Asp103 is unprotonated, a rigid Zn1-OH-Zn2 bridge results, while for neutral Asp103, a fluctuating Zn1-Zn2 distance was possible via the breaking and formation of the Zn1-OH-Zn2 bridge. The mechanistic implications of these observations are discussed in detail.

Original languageEnglish
Pages (from-to)6615-6630
Number of pages16
JournalBiochemistry
Volume41
Issue number21
DOIs
Publication statusPublished - 28 May 2002
Externally publishedYes

Fingerprint

Bacteroides fragilis
Zinc
Molecular Dynamics Simulation
Ions
Molecular dynamics
Sodium
Protonation
Solvation
Conformations
Catalytic Domain
Trajectories
Molecules
hydroxide ion
Water
Computer simulation
Enzymes
Proteins

ASJC Scopus subject areas

  • Biochemistry

Cite this

Insights into the structure and dynamics of the dinuclear zinc β-lactamase site from Bacteroides fragilis. / Suárez, Dimas; Brothers, Edward; Merz, Kenneth M.

In: Biochemistry, Vol. 41, No. 21, 28.05.2002, p. 6615-6630.

Research output: Contribution to journalArticle

@article{e6b136f1b9144c9f8381aa2f0b7cda51,
title = "Insights into the structure and dynamics of the dinuclear zinc β-lactamase site from Bacteroides fragilis",
abstract = "Herein, we report quantum chemical calculations and molecular dynamics (MD) simulations of the dinuclear form of the Bacteroides fragilis zinc β-lactamase. We studied four different configurations which differ in the protonation state of the Asp103 residue and in the presence or absence of a Zn1-OH-Zn2 bridge. The flexibility of the Zn1-OH-Zn2 bridge was studied by means of quantum mechanical (QM) calculations on cluster models while the relative stabilities of the different configurations were estimated from QM linear scaling calculations on the enzyme. Contacts between important residues (Cys 104, Asp69, Lys185, etc.), the solvation of the zinc ions, and the conformation of the active site β-hairpin loop were characterized by the MD analyses. The influence of the buried sodium ion close to the Zn2 position was investigated by carrying out a secondary simulation where the sodium ion was replaced with an internal water molecule. The comparative structural analyses among the different MD trajectories augmented with energetic calculations have demonstrated that the B. fragilis protein efficiently binds the internal Na+ ion observed crystallographically. Moreover, we found that when Asp103 is unprotonated, a rigid Zn1-OH-Zn2 bridge results, while for neutral Asp103, a fluctuating Zn1-Zn2 distance was possible via the breaking and formation of the Zn1-OH-Zn2 bridge. The mechanistic implications of these observations are discussed in detail.",
author = "Dimas Su{\'a}rez and Edward Brothers and Merz, {Kenneth M.}",
year = "2002",
month = "5",
day = "28",
doi = "10.1021/bi0121860",
language = "English",
volume = "41",
pages = "6615--6630",
journal = "Biochemistry",
issn = "0006-2960",
publisher = "American Chemical Society",
number = "21",

}

TY - JOUR

T1 - Insights into the structure and dynamics of the dinuclear zinc β-lactamase site from Bacteroides fragilis

AU - Suárez, Dimas

AU - Brothers, Edward

AU - Merz, Kenneth M.

PY - 2002/5/28

Y1 - 2002/5/28

N2 - Herein, we report quantum chemical calculations and molecular dynamics (MD) simulations of the dinuclear form of the Bacteroides fragilis zinc β-lactamase. We studied four different configurations which differ in the protonation state of the Asp103 residue and in the presence or absence of a Zn1-OH-Zn2 bridge. The flexibility of the Zn1-OH-Zn2 bridge was studied by means of quantum mechanical (QM) calculations on cluster models while the relative stabilities of the different configurations were estimated from QM linear scaling calculations on the enzyme. Contacts between important residues (Cys 104, Asp69, Lys185, etc.), the solvation of the zinc ions, and the conformation of the active site β-hairpin loop were characterized by the MD analyses. The influence of the buried sodium ion close to the Zn2 position was investigated by carrying out a secondary simulation where the sodium ion was replaced with an internal water molecule. The comparative structural analyses among the different MD trajectories augmented with energetic calculations have demonstrated that the B. fragilis protein efficiently binds the internal Na+ ion observed crystallographically. Moreover, we found that when Asp103 is unprotonated, a rigid Zn1-OH-Zn2 bridge results, while for neutral Asp103, a fluctuating Zn1-Zn2 distance was possible via the breaking and formation of the Zn1-OH-Zn2 bridge. The mechanistic implications of these observations are discussed in detail.

AB - Herein, we report quantum chemical calculations and molecular dynamics (MD) simulations of the dinuclear form of the Bacteroides fragilis zinc β-lactamase. We studied four different configurations which differ in the protonation state of the Asp103 residue and in the presence or absence of a Zn1-OH-Zn2 bridge. The flexibility of the Zn1-OH-Zn2 bridge was studied by means of quantum mechanical (QM) calculations on cluster models while the relative stabilities of the different configurations were estimated from QM linear scaling calculations on the enzyme. Contacts between important residues (Cys 104, Asp69, Lys185, etc.), the solvation of the zinc ions, and the conformation of the active site β-hairpin loop were characterized by the MD analyses. The influence of the buried sodium ion close to the Zn2 position was investigated by carrying out a secondary simulation where the sodium ion was replaced with an internal water molecule. The comparative structural analyses among the different MD trajectories augmented with energetic calculations have demonstrated that the B. fragilis protein efficiently binds the internal Na+ ion observed crystallographically. Moreover, we found that when Asp103 is unprotonated, a rigid Zn1-OH-Zn2 bridge results, while for neutral Asp103, a fluctuating Zn1-Zn2 distance was possible via the breaking and formation of the Zn1-OH-Zn2 bridge. The mechanistic implications of these observations are discussed in detail.

UR - http://www.scopus.com/inward/record.url?scp=0037188355&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037188355&partnerID=8YFLogxK

U2 - 10.1021/bi0121860

DO - 10.1021/bi0121860

M3 - Article

VL - 41

SP - 6615

EP - 6630

JO - Biochemistry

JF - Biochemistry

SN - 0006-2960

IS - 21

ER -