Molecular Dynamics Simulation of Atomic Interactions in the Vancomycin Binding Site

Olademehin, Olatunde P.; Kim, Sung Joon; Shuford, Kevin L.

doi:10.1021/acsomega.0c05353

Molecular Dynamics Simulation of Atomic Interactions in the Vancomycin Binding Site

Journal Article · Tue Dec 22 04:00:00 EST 2020 · ACS Omega

DOI:https://doi.org/10.1021/acsomega.0c05353· OSTI ID:1756771

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Baylor Univ., Waco, TX (United States); Baylor University
Howard Univ., Washington, DC (United States)
Baylor Univ., Waco, TX (United States)

Vancomycin is a glycopeptide antibiotic produced by Amycolaptopsis orientalis used to treat serious infections by Grampositive pathogens including methicillin-resistant Staphylococcus aureus. Vancomycin inhibits cell wall biosynthesis by targeting lipid II, which is the membrane-bound peptidoglycan precursor. The heptapeptide aglycon structure of vancomycin binds to the D-Ala-D-Ala of the pentapeptide stem structure in lipid II. The third residue of vancomycin aglycon is asparagine, which is not directly involved in the dipeptide binding. Nonetheless, asparagine plays a crucial role in substrate recognition, as the vancomycin analogue with asparagine substituted by aspartic acid (V_D) shows a reduction in antibacterial activities. To characterize the function of asparagine, binding of vancomycin and its aspartic-acid-substituted analogue V_D to L-Lys-D-Ala-D-Ala and L-Lys-D-Ala-D-Lac was investigated using molecular dynamic simulations. Binding interactions were analyzed using root-mean-square deviation (RMSD), two-dimensional (2D) contour plots, hydrogen bond analysis, and free energy calculations of the complexes. The analysis shows that the aspartate substitution introduced a negative charge to the binding cleft of V_D, which altered the aglycon conformation that minimized the repulsive lone pair interaction in the binding of a depsipeptide. Our findings provide new insight for the development of novel glycopeptide antibiotics against the emerging vancomycin-resistant pathogens by chemical modification at the third residue in vancomycin to improve its binding affinity to the D-Ala-D-Lac-terminated peptidoglycan in lipid II found in vancomycin-resistant enterococci and vancomycinresistant S. aureus.

View Accepted Manuscript (DOE)

Research Organization:: Baylor Univ., Waco, TX (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: SC0019327

OSTI ID:: 1756771

Alternate ID(s):: OSTI ID: 1830727

Journal Information:: ACS Omega, Journal Name: ACS Omega Journal Issue: 1 Vol. 6; ISSN 2470-1343

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: English

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