In this proposal, three complete models will be built for S100A10-Annexin A2 and S100A11-Annexin A2 tetramer complexes using the available pdb structures for annexin A2, the complexes of S100A10 with the N- terminal peptide of annexin A2, and the complex of S100A11 with the N-terminal peptide of annexin A1 and PyMOL program. The major difference among the three models is the orientation of annexin A2 relative to S100A10 or S100A11. Two or more mixed membranes of different compositions will be built using a PyMOL script. The charges and force field parameters for all the lipid molecules will be generated using Gaussian 16 and AMBER Antechamber programs. Two sandwiched simulation setups will be created to study the tetramer interaction with one membrane and with two membranes. For Setup I, the tetramer will be placed about 10 above the bottom monolayer, and then the top monolayer will be placed above the tetramer such that, when the entire system including water and counter ions is equilibrated later using NPT simulation, the top monolayer is about 20 above the tetramer. For Setup II, the top monolayer will be placed above the tetramer such that, when the entire system is equilibrated using NPT simulation, the top monolayer will be several ngstrms above the tetramer. Extensive molecular dynamics simulations will be performed for the interaction of S100A10-Annexin A2 and S100A11-AnnexinA2 tetramers with membranes of different compositions. The results will provide detailed information on the tetramer interaction with membranes at an atomic level. The simulations will provide a clear picture on the dynamic process forming microdomains rich in cholesterol and PI(4,5)P2 molecules. The results are essential to an innovative approach to cancer therapy through the design of S100A11 ligands. S100A11 ligands will be developed to block the formation of S100A11-Annexin A2 tetramer. Virtual ligand screening will be performed for S100A11 using PyRx and Autodock programs and ZINC database. Based on the docking results (poses and binding affinity), the ADMET screening, the MD simulation results on receptor-ligand complex, and MD simulation results on the receptor-target complex with the ligand docked in the middle, the top potential ligands will be selected. Collaborative research with a group of experimental scientists will be conducted for ligand synthesis, ligand binding test using ITC, and binding site conformation determination using NMR. Based on the experimental results and predicted interaction details at the atomic level using MD simulation or quantum mechanism calculations, the binding site QSAR model will be generated and the modification of the ligands will be performed iteratively to obtain S100A11 ligand with the desired functions.
S100-Annexin tetramers facilitate membrane aggregation and fusion and plasma membrane repair in cancer cells. Molecular dynamics simulations will be performed for the interaction of S100A10-Annexin A2 and S100A11-Annein A2 tetramers with membranes of different compositions. Development of S100A11 ligands to block the formation of S100A11-Annexin A2 tetramer will be carried out using a combined computational and experimental approach.
