Multi-Scale Modeling of Force Propagation in Proteins Under Mechanical Stress

Abstract

Single-molecule measurements of how proteins respond to applied force can provide valuable clues to their structure-function relationship, particularly for proteins whose role in vivo relies on an ability to resist or sense force. Interpretation of such measurements relies heavily on theoretical and computational modeling; however, the brute-force approach, molecular dynamics simulation at atomic resolution, is only feasible for timescales orders of magnitude shorter than those appropriate to experiments. Thus coarse-graining is essential for accessing experimentally relevant timescales. However, almost all coarse-grained protein models to date have been designed for the explicit purpose of studying protein folding or normal mode flexibility, and are not capable of supplying quantitative predictions about response to large applied forces. We develop a new procedure for using force measurements from all-atom molecular dynamics simulations to parameterize a coarse-grained model specifically designed for studying force response. This model has the novel feature of using the flexible Morse potential as a basis function for describing non-bonded interactions. We test the model by using it to study the kinetics of ubiquitin rupture under quasi-equilibrium forcing, and compare with experimental results.