Speaker
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The driving force for the acylation of β-lactam antibiotics by L,D-transpeptidase from Mycobacterium tuberculosis: Molecular dynamics and Quantum mechanics/molecular mechanics (QM/MM) study
Collins U. Ibeji,[a],[b] Monsurat, M. Lawal, [a] Gideon F. Tolufashe, [a] Thavendran Govender,[a] Tricia Naicker[a], Glenn E. M. Maguire,[a], [c] Gyanu Lamichhane,[d] Hendrik G. Kruger[a] and Bahareh Honarparvar[a]
Catalysis and Peptide Research Unit, School of Health Sciences, University of KwaZulu-Natal, Durban 4041, South Africa.
Department of Pure and Industrial Chemistry, Faculty of Physical Sciences, University of Nigeria, Nsukka 410001, Enugu State, Nigeria.
School of Chemistry and Physics, University of KwaZulu-Natal, Durban 4041, South Africa
Center for Tuberculosis Research, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Abstract
β-lactam antibiotics, which are used to treat infectious diseases (tuberculosis), are currently the most effective class of antibiotics. This study focused on the chemical reactivity of five- and six-membered ring systems attached to the β-lactam ring. A partially constrained Molecular dynamics for 20 ns was performed on the precomplex system. The last snapshots from the final 5 ns were used as starting structures for the unconstrained ONIOM TS calculations. The ring strain energy (RSE), force constant (FC) of amide (C—N), acylation transition states and second-order perturbation stabilization energies of 13 basic structural units of β-lactam derivatives were computed using the M06-2X and G3/B3LYP multistep method. In the ring strain calculations, an isodesmic reaction scheme was used to obtain the total energies. RSE is relatively greater in the five-(1a-2c) compared to the six-membered ring systems except for 4b, which gives a RSE that is comparable to five-membered ring lactams. These variations were also observed in the calculated inter-atomic amide bond distances (C—N), which is why the six-membered ring lactams C—N bond are more rigid than those with five-membered ring lactams. The calculated ∆G# values from the acylation reaction of the lactams (involving the S—H group of the cysteine active residue from L,D transpeptidase 2) revealed a faster rate of C—N cleavage in the five-membered ring lactams especially in the 1-2 derivative (17.58 kcal mol-1). This observation is also reflected in the calculated amide bond force constant (1.26 mDyn/A) indicating a weaker bond strength, suggesting that electronic factors (delocalization) play more role on reactivity β-lactam ring, than ring strain.
The Centre for high Performance computing (CHPC, www.chpc.ac.za) provided the computational resources (CPUs) for this work. Drawing allocation from CHEM0808 workspace (Lustre file system) on Lengau Cluster. The Gaussian09 (D01) program was used to execute the jobs. 24 cores, 1node and 48:00 hours wall time were used. Also, AMBER 14 was used for the MD studies with mpirun -np 72 -machinefile, walltime=48:00hours and ncpus=24
Keywords: β-lactam antibiotics; Transition state (TS); Ring strain energy (RSE); Force constant (FC), Activation energy.
References
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