Molecular clustering and percolation characteristics near the glass transition in aqueous trehalose and choline dihydrogen phosphate solutions.

Spatial and temporal characteristics of molecular structure in ternary solutions of trehalose and choline dihydrogen phosphate (CDHP) are studied using molecular dynamics simulations at 300 K for a range of solute concentrations with a 2 : 1 stoichiometric ratio of trehalose to CDHP. For a given molecular configuration, water molecules are classified as interior (only neighboring other water molecules) or interfacial (at least one solute neighbor). As a tagged water molecule diffuses, it dynamically exchanges between interior and interfacial type as its local environment changes, with differences in hydrogen-bond strength between different molecular species creating a persistent preference for interfacial water. At high solute concentrations, interfacial and interior water have similar diffusivity, which allows for water to collectively act as a plasticizer. The percolation threshold for water, defined as the maximum solute concentration at which there still exists a water cluster that spans the simulation box, was found to be slightly under the liquid-glass transition, estimated to be near 84.5% solute concentration based on the onset of a volume hysteresis effect, which was not previously studied in the computational literature. The systems were observed to be highly inhomogeneous, with interlaced percolating networks of water and solute coexisting at intermediate concentrations. The density of interior water was found to decrease with increasing solute concentration, creating low-density regions within the matrix.

Statistical Measures to Quantify Similarity between Molecular Dynamics Simulation Trajectories.

Molecular dynamics simulation is commonly employed to explore protein dynamics. Despite the disparate timescales between functional mechanisms and molecular dynamics (MD) trajectories, functional differences are often inferred from differences in conformational ensembles between two proteins in structure-function studies that investigate the effect of mutations. A common measure to quantify differences in dynamics is the root mean square fluctuation (RMSF) about the average position of residues defined by Cα-atoms. Using six MD trajectories describing three native/mutant pairs of beta-lactamase, we make comparisons with additional measures that include Jensen-Shannon, modifications of Kullback-Leibler divergence, and local p-values from 1-sample Kolmogorov-Smirnov tests. These additional measures require knowing a probability density function, which we estimate by using a nonparametric maximum entropy method that quantifies rare events well. The same measures are applied to distance fluctuations between Cα-atom pairs. Results from several implementations for quantitative comparison of a pair of MD trajectories are made based on fluctuations for on-residue and residue-residue local dynamics. We conclude that there is almost always a statistically significant difference between pairs of 100 ns all-atom simulations on moderate-sized proteins as evident from extraordinarily low p-values.