Simulation of Interactions between S100A(10/11)-Annexin A2 Tetramers and Membrane to Develop Efficient Binding Ligands - ABSTRACT:
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 Å
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 Å 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
Ångströms 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.
