AVS 49th International Symposium
    Biomaterials Monday Sessions
       Session BI-MoM

Paper BI-MoM4
Mapping the Free Energy State of Water in Hydration Layers and Its Importance for Ligand-Receptor Binding

Monday, November 4, 2002, 9:20 am, Room C-201

Session: Theoretical Studies of Biosurfaces/Biotribology and Biorheology
Presenter: G.W. Grahek, Clemson University
Authors: G.W. Grahek, Clemson University
R.A. Latour, Clemson University
S.J. Stuart, Clemson University
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The thermodynamic contributions of solvent molecules during ligand-receptor binding are generally believed to be very important, but relatively little is actually understood regarding how the entropy, enthalpy, and free energy of hydration layers change as a ligand approaches and docks with its receptor. We assume that both ligands and receptors perturb the thermodynamic state of their localized hydration layers, and that these effects must be superimposed on the intervening water layers as a ligand approaches its receptor. It is hypothesized that this effect may have a significant influence on the height of the activation barrier for ligand-receptor binding, and thus may serve as an important medium-range modulator of ligand-receptor binding. Based on this underlying hypothesis, we are investigating the development of statistical mechanics based molecular modeling methods to calculate the entropy, enthalpy, and free energy values of water as a function of position surrounding a designated solute molecule. Simulations have been conducted using both molecular dynamics (AMBER 6.0) and Metropolis Monte Carlo (BOSS 4.2; OPLS) methods using TIP3P and TIP5P water, respectively, and periodic boundary conditions surrounding a centralized solute molecule. Entropy, enthalpy and free energy are then mapped on a 3-dimensional grid. The simulations indicate that distinct changes do occur in the calculated free energy state of water molecules in the first two hydration layers surrounding the solute compared to bulk water. Further studies are being planned to investigate the effect of solute-solute separation distance on the intervening water layers. Following final development, these methods will be applied to actual ligand-receptor systems for the purpose of predicting the influence of water structure on binding. It is believed that these simulations may provide new insights that will facilitate drug design for specific receptor targets.