Significance of Knotted Structures for Function of Proteins and Nucleic Acids - September 17-21, 2014

Significance of Knotted Structures for Function of Proteins and Nucleic Acids

Poster Session I

20 – POS Board 20 Internal Flexibility of Clindamycin in Water and in the 50S Subunit – An in Silico Study Katarzyna Kulczycka-Mierzejewska 1 , Joanna Sadlej 2 , Joanna Trylska 3 . 1 University of Warsaw, ICM, Warsaw, Poland, 2 University of Warsaw, Department of Chemistry, Warsaw, Poland, 3 University of Warsaw, Centre of New Technology, Warsaw, Poland. Clindamycin is an antibiotic from the lincosamide class used to treat diseases caused mostly by Gram-positive bacteria. Four crystal structures of this antibiotic are currently known [1,2,3,4]. Surprisingly, a comparison of all structures revealed two substantially different conformers of clindamycin in the bound form. Previously, we used quantum mechanical methods to investigate the probable conformations of clindamycin to explain the two binding modes in the 23S ribosomal RNA of the 50S subunit [5]. Here, we used molecular dynamics methods to understand why certain nucleotide substitutions hinder the binding of lincosamides and make bacteria resistant to these antibiotics. In this work we describe the flexibility of lincosamide binding site in the 50S subunit and dynamic properties of clindamycin depending on the environment. To achieve this goal, we performed multiple 100ns long full-atom molecular dynamics simulations using the NAMD package. The following systems were simulated: clindamycin in a box of explicit water and a fragment of the 50S subunit containing clindamycin binding site with and without the A2058G mutation. The starting structure for the simulations was 3OFZ [3], containing a lower energy conformer of clindamycin. The transformation of clindamycin geometry and hydrogen bond network were analysed for each trajectory. Root mean square deviation-based clustering and atom motion correlation analysis were also applied. In the simulations we observed a transition between the two conformers of clindamycin. The results also show that the stability of clindamycin-ribosome complexes is unaffected by G2058 mutations. [1] Schlunzen et al. Nature, 413:814–821, 2001. [2] Tu et al. Cell, 121 (2):257–270, 2005

[3] Dunkle et al. PNAS, 107(40):17152–17157, 2010 [4] Morar, et al. Structure, 17 (12): 1649–1659, 2009 [5] Kulczycka-Mierzejewska et al. J. Mol. Model., 18, 2727–2740, 2011

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