Forschung im HLRN-Verbund 2011

35Figure 1: Structure of the icosahedral ionic boron clusters used (top) and their interactions with membranes (bottomleft) and proteins (bottom center and right). The approach to SMD is shown in the bottom left: The ICPis pulled into the lipid bilayer by an externally applied field, represented by the spring. The center showsIBC ions interacting with AChE, and the right is an NCP ensemble.the nucleosome core particle (NCP), will be used.AChE is important for the transmission of electricsignals in the neuron cells and it is a target enzymefor the treatment of Alzheimer disease. We foundthat AChE is inhibited by ICB [1], which is surprising,as the ICB are negatively charged and the naturalsubstrate is positively charged. NCP is themolecular building block of the chromatin presentin the nuclei of eukaryotic cells. We have found thatIBC accumulate in the nuclei of the cells, probablyon NCP. It likely that the anions interact preferentiallywith the positively charged histones. We haveperformed MD simulations of NCP [3], but dockingstudies with IBC have not yet been conductedon this system. We plan to investigate the bindingof IBC to AChE and with the histone proteinsin NCP by using MD simulations. MD will be usedto analyze preferential binding of the ICB to specificsites on the protein surface, in order to learnabout the specific propensity of the ions to bind tospecific amino acids. Subsequently, the diffusionof the boron cluster into the AchE active site willbe analyzed by calculating the free energy barrierof diffusion and free energy of binding. We expectto obtain information on binding constants andconformational changes, which can be comparedwith experimental data from enzyme inhibition andNMR spectroscopy.More Information1. Awad, D., L. Damian, M. Winterhalter, G. Gabel,D., D. Awad, T. Schaffran, D. Radovan, D. Daraban,L. Damian, M. Winterhalter, G. Karlsson,and K. Edwards. 2007. The Anionic BoronCluster (B 12 H 11 SH(2-) as a Means To TriggerRelease of Liposome Contents. ChemMed-Chem 2:51-53.2. Schaffran, T., E. Justus, M. Elfert, T. Chen, andD. Gabel. 2009. Toxicity of N,N,N- trialkylammoniododecaboratesas new anions of ionic liquidsin cellular, liposomal and enzymatic testsystems. Green Chem 11:1458-1464.3. Roccatano D., A. Barthel, M. Zacharias. 2007.Structural flexibility of the nucleosome core particleat atomic resolution studied by moleculardynamics simulations. Biopolymers, 85, 401-421.FundingUniversity of BremenChemie