Molecular dynamics studies on the folding dynamics of poly-phenylacetylene, a non-biological polymer with a helical, folded state

Molecular Dynamics simulations of all-atom models of polymeric systems provide a unique perspective into the molecular folding dynamics at the bulk ensemble level as well as the investigation of single molecule events. We have created several theoretical models of a non biological oligomer, poly-phenylacetylene (pPA), with a unique, stable helical native state incorporating increasing levels of molecular complexity. This class of Foldamers, also known as phenylene ethynylene oligomers, folds via non-exponential kinetics expressed in the cumulative folding time distribution; observed independently via molecular dynamics simulations and also experimentally using laser temperature jump fluorescence methods.; We outline computational methods to probe the kinetic behavior of pPA oligomers of different lengths, specifically 12-mers and 20-mers, each from an ensemble of folding trajectories in implicit solvent. The length dependent folding mechanism is extracted from a non-linear fit to a minimalist kinetic model derived from the Law of Mass Action. We find that the pPA 12-mer folds via a three-state process in which the fully extended chain collapses to an intermediate kinetic state with partially helical intermediate structures and topologically diverse conformations including beta-like strands and also knots. Quantitative agreement between the experimentally observable rate constant and the rate measured from our simulations serves to validate the theoretical model for its predictive value.; The kinetic mechanism by which the pPA 20-mer chains fold is also extracted from a fit to a 4-state kinetic model derived from the Law of Mass Action. One important and striking difference observed in the 20-mer chains compared to the 12-mers is the appearance of a trapped kinetic phase in the cumulative folding time distribution. We present structural evidence implicating a very topologically diverse set of non-native conformations contributing to the trapped kinetic phase. Topologically similar structures to those observed in the 12-mer chains are also found in the 20-mer chains, including longer beta-like strands and more entangled knots, in addition to other structures not observed in the 12-mer data set.; A more complex computational model of poly-phenylacetylene is used to study the folding mechanism of the model 12-mer chains in explicit solvent. We model the folding of these pPA 12-mer chains in a broad range of solvents, specifically acetonitrile, chloroform, methanol, and water. We observed folding propensities consistent with experiments, in which chloroform acts as a denaturant preventing the pPA chains from folding. Water, on the other hand is a very poor solvent and promotes aggregation, which is consistent with what we observe in our simulations. Acetonitrile and methanol are intermediate between these two extremes and are found to be optimal (theta) solvents to promote the folding of the pPA chains.