Quantitative Analysis of Water Dynamics in and near Proteins

Proteins exist in aqueous solution. Hydration can be viewed as a description of how the protein disturbs the structure and dynamics of water. Water molecules in the vicinity of proteins are generally seen as either external or internal water molecules. Internal water molecules occupy cavities, exchange on a time-scale of 0.1--10 microseconds with bulk water, are almost as conserved as amino acids, and are therefore likely to be important for function. External water molecules tend to be found in protein crevices and are typically not conserved, even between crystal structures of the same protein. We introduce a method to analyze the behavior of water molecules in molecular dynamics (MD) simulations in terms of graphs. The graph encodes a simple hopping model: Nodes in the graph correspond to hydration sites, typically defined from the density in computer simulations or observed water sites in crystal structures. Directed edges correspond to transitions (“hops”) between sites, with transition rates computed from MD simulations. We apply this analysis to the water-filled cavity of intestinal fatty acid binding protein (I-FABP) in its apo and holo (palmitate-bound) state. This demonstrates how ligand binding influences the well-defined set of hydration sites in and around the protein's cavity. The ligand displaces a number of hydration sites but does not affect others close by. The parameters extracted from the network model allow us to model the movement of water molecules with a Markov Chain Monte Carlo model. The graphical construct reproduces the average site occupancy found in the MD simulations and the fluctuations of the occupancy.This approach suggests new types of sampling and analysis that can be applied to extend the range of molecular dynamics models and the role of water in ligand binding.