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

Dimas Suárez, Edward Brothers, Kenneth M. Merz

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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
Issue number21
Publication statusPublished - 28 May 2002
Externally publishedYes


ASJC Scopus subject areas

  • Biochemistry

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