A molecular dynamics simulation of reactant mobility in an amorphous formulation of a peptide in...

The reaction pathways available for chemical decomposition in amorphous solids are determined in part by the relative mobilities of the potential reactants. In this study, molecular dynamics simulations of amorphous glasses of polyvinylpyrrolidone (PVP) containing small amounts of water, ammonia, and a small peptide, Phe-Asn-Gly, have been performed over periods of up to 100 ns to monitor the aging processes and associated structural and dynamic properties of the PVP segments and embedded solutes. Glass transition temperatures, Tg, were detected by changes in slopes of the volume-temperature profiles and the internal energy-temperature profiles for the inherent structures upon cooling at different rates. Analyses of the molecular trajectories below Tg reveal both temporal and spatial heterogeneity in polymer and solute mobility, with each molecule or part of a molecule displaying quite different relaxation behaviors for translational, rotational, and/or conformational motions. Rotations of individual polymer segments on the time scale up to 100 ns, though far from complete, are described by the Kohlrausch-Williams-Watts stretched exponential function with relaxation times tau on the order of 10-2.8 x 10(4) micros at an averaged stretching parameter beta of 0.39. The rotation rates are, on the average, faster for the side chains and for segments near the ends of the chains than for the backbones and segments near the middle of the chains. In contrast to their behavior in water, solute diffusive motions in the glassy polymer exhibit non-Einsteinian behavior over the time scale of the simulations characterized by two types of motion: (1) entrapments within relatively fluid microdomains surrounded by a matrix of relatively immobile polymer chains; and (2) jumps between microdomains with greater probability of hopping back to the solute's previous location. The average jump length and frequency are highly dependent on solute size, being much smaller for the tripeptide, Phe-Asn-Gly, than for water and ammonia. The diffusivities of water and ammonia, solutes capable of forming hydrogen bonds with the lactam residues within the polymer segments, are significantly reduced by strong electrostatic interactions. The conformational preferences of Phe-Asn-Gly were compared in the amorphous polymer and water to detect differences in the degree to which the tripeptide may be predisposed toward deamidation of the asparagine side chain in these environments. Although only minor differences are evident in peptide conformation, the conformational dynamics for the peptide embedded in the glassy polymer are characterized by a higher energy barrier between conformational states and 2.5-44-fold larger relaxation times for the dihedral angles of interest than in water. However, in the context of peptide deamidation, these differences may be of secondary importance in comparison to the more than two to three orders of magnitude reduction in the diffusivities of water, ammonia, and the tripeptide in PVP.