We present a web toolkit STructure mapper and Online Coarse-graining Kit for setting up coarse-grained molecular simulations. The kit consists of two tools: structure mapping and Boltzmann inversion tools. The aim of the first tool is to define a molecular mapping from high, for example, all-atom, to low, that is, coarse-grained, resolution. Using a graphical user interface it generates input files, which are compatible with standard coarse-graining packages, for example, Versatile Object-oriented Toolkit for Coarse-graining Applications and DL_CGMAP. Our second tool generates effective potentials for coarse-grained simulations preserving the structural properties, for example, radial distribution functions, of the underlying higher resolution model. The required distribution functions can be provided by any simulation package. Simulations are performed on a local machine and only the distributions are uploaded to the server. The applicability of the toolkit is validated by mapping atomistic pentane and polyalanine molecules to a coarse-grained representation. Effective potentials are derived for systems of TIP3P (transferable intermolecular potential 3 point) water molecules and salt solution. The presented coarse-graining web toolkit is available at http://stock.cmm.ki.si.
F.23 Development of new system-wide, normative and programme solutions, and methods
COBISS.SI-ID: 37695493We present a multiscale approach AdResS used for simulation of DNA molecule in 1M NaCl salt solution. We have taken a special care of collective properties of the system such as dielectric constant which repesent a sensitive test for the multiscale approach we developed.
B.03 Paper at an international scientific conference
COBISS.SI-ID: 5704730We developed LiSiCA (Ligand Similarity using Clique Algorithm) - ligand-based virtual screening software that uses a fast maximum clique algorithm to find two- and three-dimensional similarities between pairs of molecules and appliedit to the discovery of novel potent butyrylcholinesterase inhibitors. LiSiCA, which runs in parallel on multiple processor cores, was successfully tested on the Database of Useful Decoys - Enhanced, to evaluate its ability todiscriminate active molecules from decoys. We then applied LiSiCA for the discovery of novel inhibitors of human butyrylcholinesterase, a promising anti-Alzheimer target, using a known inhibitor as the reference compound. We demonstrated that LiSiCA is capable of finding potent nanomolar inhibitors, whose scaffolds differed from the reference compound, thus proving its abilityfor scaffold hopping and usefulness in drug discovery.
F.23 Development of new system-wide, normative and programme solutions, and methods
COBISS.SI-ID: 3893361Proteins often exist only as apo structures (unligated) in the Protein Data Bank, with their corresponding holo structures (with ligands) unavailable. However, apoproteins may not represent the amino-acid residue arrangement upon ligand binding well, which is especially problematic for molecular docking. We developed the ProBiS-CHARMMing web interface by connecting the ProBiS (http://probis.cmm.ki.si) and CHARMMing (http://www.charmining.org) web servers into one functional unit that enables prediction of protein-ligand complexes and allows for their geometry optimization and interaction energy calculation. The ProBiS web server predicts ligands (small compounds, proteins, nucleic acids, and single-atom ligands) that may bind to a query protein. This is achieved by comparing its surface structure against a nonredundant database of protein structures and finding those that have binding sites similar to that of the query protein. Existing ligands found in the similar binding sites are then transposed to the query according to predictions from ProBiS. The CHARMMing web server enables, among other things, minimization and potential energy calculation for a wide variety of biomolecular systems, and it is used here to optimize the geometry of the predicted protein ligand complex structures using the CHARMM force field and to calculate their interaction energies with the corresponding query proteins. We show how ProBiS-CHARMMing can be used to predict ligands and their poses for a particular binding site, and minimize the predicted protein ligand complexes to obtain representations of holoproteins. The ProBiS-CHA_RMMing web interface is freely available for academic users at http://probis. nih.gov.
F.23 Development of new system-wide, normative and programme solutions, and methods
COBISS.SI-ID: 5806106In the presentation our results of structure-based design of novel DNA gyrase B inhibitors which is a validated target for development of novel antibacterials were revealed. The inhbitors from the various structural classes: indolinone-2-ones, 2-2-amino-4-(2,4 dihydroxyphenyl)thiazoles, 4’-methyl-N2-phenyl-[4,5’-bithiazole]-2,2’-diamines, 4,5-dibromopyrrolamides, indolamides and 4,5,6,7-tetrahydrobenzo[1,2-d]thiazoles were characterised also with biophysical approaches (differential scanning fluorimetry, surface plasmon resonance, microscale thermophoresis and protein crystallography, in the complex with DNA gyrase.
B.03 Paper at an international scientific conference
COBISS.SI-ID: 5841178