Book of Abstracts: Albany 2009
June 16-20 2009
© Adenine Press (2008)
RNA Simulations - Part 3: Mapping Solvent Binding Sites of the Aminoglycoside Bacterial rRNA A-site Target
Aminoglycosides antibiotics provoke lethal translation errors by specifically binding to the bacterial ribosomal A-site. Yet, due to serious side effects, they are often considered to be the last resort treatment in case of severe bacterial infections. Hence, in order to improve the efficiency of these drugs, we still need to better understand their binding features that are largely but not solely governed by electrostatic complementarity.
Here, we use explicit solvent molecular dynamics (MD) simulations to map ions (NH4+, K+) and water binding sites of a free bacterial A-site and their aminoglycoside complexes. Solvent binding maps are presented as neutron-diffraction-like densities revealing, besides heavy atom positions, the most favorable locations of NH4+ and H2O hydrogen atoms (see figure). It was found that the main NH4+ cation binding site matches the key ?NH3+ anchor point of the conserved neamine cycle II. Moreover, this site appears specific to NH4+ over K+ cations that, even though they carry a similar charge, differ in their ability to form H-bond networks. Besides cation recognition sites, water binding sites overlap as well with some aminoglycoside direct contacts. Hence, we showed that explicit solvent MD simulations are able to efficiently locate major drug binding sites. As an outcome, the characterization of solvent binding sites (including hydrogen atom positions) and associated H-bond networks should be included in ?rational? drug design strategies involving aminoglycosides and related drugs.
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