Computational model for the acylation step of the β-lactam ring: Potential application for L,D-transpeptidase 2 in mycobacterium tuberculosis

Zeynab Fakhar, Thavendran Govender, Gyanu Lamichhane, Glenn E M Maguire, Hendrik G. Kruger, Bahareh Honarparvar

Research output: Contribution to journalArticle

Abstract

Tuberculosis (TB) remains a major global health quandary. The peptidoglycan layer of mycobacterium tuberculosis (M.tb) consists of glycoproteins that are crosslinked by transpeptidases. Carbapenems are a subfamily of β-lactam antibiotics that inactivate the L,D-transpeptidase enzyme effectively (3 → 3 crosslinks). The mechanism of ring opening and thioester bond formation between the β-lactam core and the Cys354 active residue (for L,D-transpeptidase) during the acylation step is still the subject of considerable discussion. Herein, an acylation mechanism is proposed through four possible model transition states (TS), namely four membered-ring (TS-4, TS-4-His and TS-4-water) and six membered-ring (TS-6-water) transition states. The quantum chemical calculations for these TS models were performed with Density Functional Theory (DFT) using the B3LYP functional and the 6-31 + G(d) basis set. The calculated thermodynamic properties such as relative reaction energies (ΔEreaction), Gibbs free energies (ΔG), enthalpy energies (ΔH) and entropy contributions (ΔS) were reported at 298.15 K for the four considered pathways. The highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) were calculated to evaluate and compare the chemical reactivities of the considered TS models. Natural bond orbital (NBO) analysis was performed to determine the effective intermolecular orbital interactions E(2) derived by the second perturbation theory. The chemical hardness (η) and softness (S) and Fukui indices (fk +, fk ) of these TS models were compared to confirm the feasibility and preference of the considered pathways. The outcome of this study will pave the way for an improved understanding of the LDT/carbapenem acylation reaction at a molecular level.

Original languageEnglish (US)
Pages (from-to)94-102
Number of pages9
JournalJournal of Molecular Structure
Volume1128
DOIs
StatePublished - Jan 15 2017

Fingerprint

Peptidyl Transferases
Acylation
beta-Lactams
Carbapenems
Water
Peptidoglycan
Hardness
Entropy
Thermodynamics
Mycobacterium tuberculosis
Glycoproteins
Tuberculosis
Outcome Assessment (Health Care)
Anti-Bacterial Agents
Enzymes
Global Health

Keywords

  • Chemical hardness (η)
  • Density Functional Theory (DFT)
  • Fukui indices (f , f )
  • L,D-transpeptidase
  • Mycobacterium tuberculosis (Mtb)
  • Softness (S)
  • β-lactam

ASJC Scopus subject areas

  • Analytical Chemistry
  • Spectroscopy
  • Organic Chemistry
  • Inorganic Chemistry

Cite this

Computational model for the acylation step of the β-lactam ring : Potential application for L,D-transpeptidase 2 in mycobacterium tuberculosis. / Fakhar, Zeynab; Govender, Thavendran; Lamichhane, Gyanu; Maguire, Glenn E M; Kruger, Hendrik G.; Honarparvar, Bahareh.

In: Journal of Molecular Structure, Vol. 1128, 15.01.2017, p. 94-102.

Research output: Contribution to journalArticle

Fakhar, Zeynab; Govender, Thavendran; Lamichhane, Gyanu; Maguire, Glenn E M; Kruger, Hendrik G.; Honarparvar, Bahareh / Computational model for the acylation step of the β-lactam ring : Potential application for L,D-transpeptidase 2 in mycobacterium tuberculosis.

In: Journal of Molecular Structure, Vol. 1128, 15.01.2017, p. 94-102.

Research output: Contribution to journalArticle

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