Foldamer simulations: Novel computational methods and applications to poly-phenylacetylene oligomers

Abstract

We apply several methods to probe the ensemble kinetic and structural properties of a model system of poly-phenylacetylene (pPA) oligomer folding trajectories. The kinetic methods employed included a brute force accounting of conformations, a Markovian state matrix method, and a nonlinear least squares fit to a minimalist kinetic model used to extract the folding time. Each method gave similar measures for the folding time of the 12-mer chain, calculated to be on the order of 7 ns for the complete folding of the chain from an extended conformation. Utilizing both a linear and a nonlinear scaling relationship between the viscosity and the folding time to correct for a low simulation viscosity, we obtain an upper and a lower bound for the approximate folding time within the range 70 ns<tau<350 ns. This is in agreement with the experimentally measured folding time on the order of 160 ns. The kinetic model used to fit the kinetic behavior of the ensemble of trajectories provides a framework to describe the bulk folding mechanism. We were able to identify two unique clusters of conformations that provide a structural basis to account for the appearance of a kinetic intermediate in the mechanism. We discuss the implications of these findings in the context of helix-coil theory.