High temperature unfolding simulations of the TRPZ1 peptide

Abstract

We report high temperature molecular dynamics simulations of the unfolding of the TRPZ1 peptide using explicit model for the solvent. The system has been simulated for a total of 6 μs with 100-ns minimal continuous stretche; trajectory. The populated states along the simulations are identified by monitoring multiple observables, probing both structure and the flexibility of the conformations. Several unfolding and refolding transition pathways are sampled and analyz The unfolding process of the peptide occurs in two steps because of the accumulation of a metastable on-pathway intermedi state stabilized by two native backbone hydrogen bonds assisted by nonnative hydrophobic interactions between the tr tophan side chains. Analysis of the un/folding kinetics and classical commitment probability calculations on the conformati extracted from the transition pathways show that the rate-limiting step for unfolding is the disruption of the ordered na hydrophobic packing (Trp-zip motif) leading from the native to the intermediate state. But, the speed of the folding proces mainly determined by the transition from the completely unfolded state to the intermediate and specifically by the closure of hairpin loop driven by formation of two native backbone hydrogen bonds and hydrophobic contacts between tryptophan r dues. The temperature dependence of the unfolding time provides an estimate of the unfolding activation enthalpy that i agreement with experiments. The unfolding time extrapolated to room temperature is in agreement with the experimental d as well, thus providing a further validation to the analysis reported here © 2008 by the Biophysical Society.