MD Simulation Study on Ligand Binding, Ion Permeation and Ionic Force Field on Leadership Level Platform

Yun Luo
Seminar

Recent advances in computational power make the combination of theory, modeling and simulations a powerful tool for deepening our understanding of life science and material science. Classical molecular dynamics (MD) simulations of large-scale with advanced phase sampling strategy and accurate potential energy functions are crucial for exploring the behavior of biomolecules in physiological environment. In our recent studies, we explore the methodologies and applications of MD simulations on the leadership level platform Blue Gene/P in biological system, force field development, as well as in material science.

In biomolecular system, the calcium binding protein Calbindin D9k is chosen as a model system for studying the molecular mechanism of cooperativity(1). Binding is characterized in terms of a potential of mean force (PMF) as a function of two variables: the distance r between the ion, and the binding pocket, and the root-mean-square deviation (RMSD) of the conformation of the EF-hand relative to its ion-bound structure. The PMF is calculated using a novel two-dimensional replica-exchange molecular dynamics (MD) umbrella sampling scheme, which is developed and implemented in the program CHARMM to increase the configuration space sampling. Using 2048 replicas on Blue Gene/P, the 2D-PMF/REMD calculation for the binding the second calcium ion converges within 800 ps. The absolute binding free energy of a second ion to a singly occupied calbindin calculated from the 2D-PMF following the statistical mechanical formulation of noncovalent association(2) is -9.4 kcal/mol, in excellent agreement with the experimental value(3). The 2D-PMF/REMD simulations will be extended to provide important information about the molecular basis of calcium binding cooperativity. In the force field development, a novel methodology for osmotic pressure calculation is developed and applied to both nonpolarizable and polarizable Drude model(4). The study shows that the osmotic pressure is a powerful route for validating and parametrizing atomic force fields. In particular, the key thermodynamic and transport properties of ionic Drude models are calculated in large-scale system using dual-Langevin thermostat scheme with the high-performance scalable program NAMD(5). In the material science, the allocation on Intrepid for the IonPermeation project has allowed us to advance significantly our research on Reverse osmosis (RO) membranes. RO membranes, based on aromatic polyamide thin-film composites (TFC), are extensively used for desalination and purification of sea water and brackish water. In our research, we use large-scale MD simulation to probe and reveal the polymerization process and transport properties of the RO membranes at the atomic level. The result shows that computer simulation is an effective tool to investigate the relationship between the microscopic structure of materials and their macroscopic properties, thus can help to advance the new material design.

(1)Marchand S. and Roux B. Protein Struct. Funct. Genet. 1998, 33, 265-284.
(2)Woo H. and Roux B., PNAS, 2005, 19, 6825.
(3)Linse S. et al. Biochemistry 1991, 30, 154.
(4)Luo Y. and Roux B. J. Phys. Chem. Lett., 2010, 1, 183.
(5)Jiang, W., et al. J. Phys. Chem. Lett. 2011, 2, 87.

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