Journal of Molecular Modeling

, 15:133 | Cite as

Molecular dynamic simulations of the metallo-beta-lactamase from Bacteroides fragilis in the presence and absence of a tight-binding inhibitor

  • Freddie R. SalsburyJr.Email author
  • Michael W. Crowder
  • Stephen F. Kingsmore
  • James J. A. Huntley
Original Paper


The beta-lactam-based antibiotics are among the most prescribed and effective antibacterial agents. Widespread use of these antibiotics, however, has created tremendous pressure for the emergence of resistance mechanisms in bacteria. The most common cause of antibiotic resistance is bacterial production of actamases that efficiently degrade antibiotics. The metallo-beta-lactamases are of particular clinical concern due to their transference between bacterial strains. We used molecular dynamics (MD) simulations to further study the conformational changes that occur due to binding of an inhibitor to the dicanzinc metallo-beta-lactamase from Bacteroides fragilis. Our studies confirm previous findings that the major flap is a major source of plasticity within the active site, therefore its dynamic response should be considered in drug development. However, our results also suggest the need for care in using MD simulations in evaluating loop mobility, both due to relaxation times and to the need to accurately model the zinc active site. Our study also reveals two new robust responses to ligand binding. First, there are specific localized changes in the zinc active site—a local loop flip—due to ligand intercalation that may be critical to the function of this enzyme. Second, inhibitor binding perturbs the dynamics throughout the protein, without otherwise perturbing the enzyme structure. These dynamic perturbations radiate outward from the active site and their existence suggests that long-range communication and dynamics may be important in the activity of this enzyme.


Drug resistance Long-rang communication Metallo-beta-lactamases Molecular dynamics 



Some of these calculations were performed on the DEAC cluster at Wake Forest University ( We thank the WFU Information Systems for their support of the cluster, WFU’s Department of Physics and Associate Provost for Research for their funding of the cluster, and IBM for their generous support through a SUR grant to provide disk space. J.H. acknowledges partial support of this publication by NIH Grant Number RR-16480 from the NM-INBRE Program of the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH). We thank an anonymous reviewer for suggesting the hydrogen bond analysis.

Supplementary material

894_2008_410_Fig1_ESM.gif (820 kb)
Figure S1

Structural comparison of Apo, pose 2 and the structure with the longest zinc–zinc distance. The centroids of the most populated clusters in the apo (gray), and pose 2 (red) simulations are depicted along with the structure with the largest zinc–zinc distance (orange), which is found in pose 2. The protein is depicted in the new cartoon representation, and the zinc atoms in vdW representation (GIF 819 KB).

894_2008_410_Fig1_ESM.tif (721 kb)
(TIF 721 KB)
894_2008_410_Fig2_ESM.gif (1.1 mb)
Figure S2

Detailed structural comparison of Apo, pose 2 and the structure with the longest zinc–zinc distance. As Fig. S1, but zoomed in with all atoms within 5 Å of the zinc atoms depicted in a bonded representation to highlight the loop flip and the slight structural changes at the zinc site (GIF 109 MB).

894_2008_410_Fig2_ESM.tif (1.2 mb)
(TIF 115MB)


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Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Freddie R. SalsburyJr.
    • 1
    Email author
  • Michael W. Crowder
    • 2
  • Stephen F. Kingsmore
    • 3
  • James J. A. Huntley
    • 3
  1. 1.Department of PhysicsWake Forest UniversityWinston SalemUSA
  2. 2.Department of Chemistry and BiochemistryMiami UniversityOxfordUSA
  3. 3.National Center for Genome ResourcesSanta FeUSA

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