Past Event: Oden Institute Seminar

Insights into the Initiation of Protein Unfolding via a Long Helix

Steven Kreuzer, University of Texas at Austin

Abstract

Abstract: Protein behavior and unfolding under applied external loads is critical for many biological processes, from muscle contraction to metastasis. As a fundamental protein building block, α-helices are key to many of these processes. In this talk, I will describe constant-force molecular dynamics simulations that, when combined with Milestoning analysis, provide insight into the initiation of helix unfolding for an 'average' helical residue. Here, a ~100 amino-acid long helix is considered. Transitions of individual amino acids (averaged over the helix’s interior residues) between different helical secondary structure states are examined via consideration of the instantaneous status of hydrogen bonds spanning each residue. Dense kinetic networks are constructed that, together with Milestoning analysis, estimate the overall kinetics of early breakage events. Network analysis and identification of MaxFlux pathways illustrate that load impacts both the mechanisms as well as the time scales of helix unfolding. We demonstrate that, perhaps counter-intuitively, at relatively high (100pN) load levels the principal intermediate is the 310-helix, while at relatively low (10pN) levels the pi-helix—a 'fatter' helical variant—is significantly populated, albeit not as an unfolding intermediate. Different degrees of coarse graining are examined, revealing that the calculated rate of unfolding—on the order of ~5ns for a single amino-acid unfolding event—is remarkably invariant to changes in the coarsening. Furthermore, hydrogen bonds prove to be much faster coarse variables (by about 2 orders of magnitude) than backbone torsional transitions, thereby gating unfolding. *refreshments at 1:45 pm