Crack Propagation on Networks: A Model for Protein Unfolding

Abstract

The manner in which proteins respond under an applied force is of direct biological significance, as a complete understanding of the mechanical, regulatory and signaling properties of many proteins depend not only on their native state conformations, but also on the nature of partially unfolded intermediate states that become populated under an applied force. The inability of molecular dynamics simulation to reach timescales probed experimentally has led some to use coarse-grained elastic network models to study unfolding properties. While computationally efficient, these models have been limited to the study of the native state. Building on a recently developed method called geometric targeting [1], we use a constraint-based, all-atom representation to generate complete unfolding pathways. The model uses a simplified potential to maintain proper stereochemistry and represents hydrogen bonds, salt bridges and hydrophobic interactions as breakable inequality constraints. By iteratively increasing the extension of a protein and breaking constraints according to a set of simple rules, we demonstrate that the simple and intuitive model of protein unfolding as crack propagation on a constraint network is sufficient to capture the unfolding pathways and experimentally observed intermediates of a diverse set of proteins far from their native states. [1] Farrell, D. W., K. Speranskiy, and M. F. Thorpe. 2010. Generating stereochemically acceptable protein pathways. Proteins: Structure, Function, and Bioinformatics 78:2908-2921.