By Tan Do, Chemistry; Luiz Oliveira, University of Cincinnati
Advisor: George Stan
Abstract: Molecular knots can occur in biological macromolecules such as DNA, RNA and proteins. It has already been shown that difficulties in degrading knotted proteins can result in a variety of neurodegenerative diseases. However, the details of unfolding and translocation of knotted substrate proteins (SP) by ATP-dependent proteases (ATPase) nanomachines are not fully understood. The central focus of this computational study is to investigate the mechanism of translocation and unfolding of knotted SP by bacterial caseinolytic protease (Clp) ATPases. With this goal, we use an implicit solvent model to perform Langevin dynamics simulations of unfolding and translocation of knotted substrate proteins (SPs), with knots of three different types, through the narrow central pore of the ATPase ClpY, By conducting an analysis of the time evolution of native and non-native contacts , we find that the non-native contacts play a fundamental role in determining knot size and controlling knot diffusion. We also observe, in good agreement with results from knotted biopolymers, that the translocation of knotted proteins occurs in two main regimes, tension propagation and tail retraction.