Protein mechanics probed using simple molecular models

Background

Single molecule experimental techniques such as optical tweezers or atomic force microscopy can be used as a direct probe of the mechanical unfolding/folding of individual proteins. They are also a means to investigate free energy landscapes. Single-protein force spectroscopy alone provides limited information; theoretical models relate measurements to thermodynamic and kinetic properties of the protein, but they do not reveal atomic level information. By building a molecular model of the protein and probing its properties through numerical simulation, one can gauge the response to an external force for individual interatomic interactions and determine structures along the unfolding pathway. When used in combination, single molecule force probes and molecular simulations have contributed to uncover the rich behavior of proteins when subjected to mechanical force.

Scope of review

We focus on how simplified protein models have been instrumental in showing how the general properties of the free energy landscape of a protein relate to its response to mechanical perturbations. We discuss the role of simple or toy protein models to explore the complexity of free energy landscapes and highlight important conceptual issues that more chemically accurate models with all-atom representations of proteins and solvent cannot easily address.

Major conclusions

Native-centric, coarse-grained models, despite their simplifications in chemical detail compared to all-atom models, can be used to reproduce and interpret experimental results. They have also highlighted instances where the theoretical framework used to interpret single molecule data is too simple. However, in some cases where non-native contacts are important on unfolding, these simple models are not able to reproduce the experimental findings.

General significance

Mechanical forces are ubiquitous in the cell and it is increasingly clear that the way a protein responds to mechanical perturbation is important.