J1-5455 — Annual report 2015
1.
Adaptive resolution simulation of a DNA molecule in salt solution

We present a multiscale simulation of a DNA molecule in 1 M NaCl salt solution environment, employing the adaptive resolution simulation approach that allows the solvent molecules, i.e., water and ions, to change their resolution from atomistic to coarse-grained and vice versa adaptively on-the-fly. The region of high resolution moves together with the DNA center-of-mass so that the DNA itself is always modeled at high resolution. We show that our multiscale simulations yield a stable DNA-solution system, with statistical properties similar to those produced by the conventional all-atom molecular dynamics simulation. Special attention is given to the collective properties, such as the dielectric constant, as they provide a sensitive quality measure of our multiscale approach.

COBISS.SI-ID: 5756698
2.
Discovery of 4,5,6,7-tetrahydrobenzo[1,2-d]thiazoles as novel DNA gyrase inhibitors targeting the ATP-binding site

The bacterial type IIA topoisomerases, DNA gyrase and topoisomerase IV, are essential enzymes that control the topological state of DNA during replicationand validated antibacterial drug targets. Growing resistance against fluoroquinolones, that also target these enzymes, limits their therapeutic potential and stimulates the search for novel inhibitor classes targeting their ATP-binding sites. Starting from a library of marine alkaloid oroidin analogs, we identified low micromolar inhibitors of E. coli DNA gyrase, based on the 5,6,7,8-tetrahydroquinazoline and 4,5,6,7-tetrahydrobenzo[1,2-d]thiazole scaffolds. Structure-based optimization of the initial hits resulted in low nanomolar E. coli DNA gyrase inhibitors, some of which exhibited micromolar inhibition of E. coli topoisomerase IV and of S. aureus homologs. Studies of the binding modes of inhibitors in the ATP-binding sites of the E. coli DNA gyrase support the observed structure-activity relationship. Some of the compounds possessed modest antibacterial activity against Gram positive bacterial strains, while their evaluation against wild-type, impA and ŽtolC E. coli strains suggests that they are efflux pump substrates and/or do not possess the physico-chemical properties necessary for cell wall penetration. Our study provides a rationale for optimization of this class of compounds towards balanced dual DNA gyrase and topoisomerase IV inhibitors with antibacterial activity.

COBISS.SI-ID: 3889009
3.
Fast rotational motion of water molecules increases ordering of hydrophobes in solutions and may cause hydrophobic chains to collapse

Using the molecular dynamics simulations with separate thermostats for translational and rotational degrees of freedom, we investigate the effects of water's rotational motion on the interaction among Lennard-Jones solutes. The situation with rotational temperature higher than the translational one (T-R ) T-T) is mimicking the effects of microwaves on model solutions. Molecular dynamics simulations suggest that solutions of Lennard-Jones solutes become increasingly more structured with the rise in T-R, while keeping the T-T constant. This is evidenced by an increase of the first and the second peak of the solute-solute radial distribution function. In addition, the first peak moves toward slightly larger distances; the effect seems to be caused by the destabilization of water molecules in the first hydration shell around hydrophobic solutes. More evidence of strong effects of the rotationally excited water is provided by the simulations of short hydrophobic polymers, which upon an increase in T-R assume more compact conformations. In these simulations, we see the re-distribution of water molecules, which escape from hydrophobic "pockets" to better solvate the solvent exposed monomers.

COBISS.SI-ID: 1536690627