Abstract
Mechanical unfolding of a single domain of loop-truncated superoxide dismutase protein has been simulated via force spectroscopy techniques with both all-atom (AA) models and several coarse-grained models having different levels of resolution: A Gō model containing all heavy atoms in the protein (HA-Gō), the associative memory, water mediated, structure and energy model (AWSEM) which has 3 interaction sites per amino acid, and a Gō model containing only one interaction site per amino acid at the Cα position (Cα-Gō). To systematically compare results across models, the scales of time, energy, and force had to be suitably renormalized in each model. Surprisingly, the HA-Gō model gives the softest protein, exhibiting much smaller force peaks than all other models after the above renormalization. Clustering to render a structural taxonomy as the protein unfolds showed that the AA, HA-Gō, and Cα-Gō models exhibit a single pathway for early unfolding, which eventually bifurcates repeatedly to multiple branches only after the protein is about half-unfolded. The AWSEM model shows a single dominant unfolding pathway over the whole range of unfolding, in contrast to all other models. TM alignment, clustering analysis, and native contact maps show that the AWSEM pathway has however the most structural similarity to the AA model at high nativeness, but the least structural similarity to the AA model at low nativeness. In comparison to the AA model, the sequence of native contact breakage is best predicted by the HA-Gō model. All models consistently predict a similar unfolding mechanism for early force-induced unfolding events, but diverge in their predictions for late stage unfolding events when the protein is more significantly disordered.
Highlights
No other scientific discipline has been so challenged to match the standard of physics-based simplicity as molecular and cell biology, perhaps in parts due to the inherent complexity of the systems under study and to our incomplete knowledge of the structure and function of the living cell
Our objective in this paper is to evaluate several CG models in Steered molecular dynamics (SMD) simulations by comparing the unfolding mechanisms predicted by each model to those predicted by a reference all-atom simulation under the same conditions
We construct scaling procedures such that the time, energy, and force scales can be meaningfully compared, and we develop several different metrics that each provide a different viewpoint of the unfolding dynamics
Summary
No other scientific discipline has been so challenged to match the standard of physics-based simplicity as molecular and cell biology, perhaps in parts due to the inherent complexity of the systems under study and to our incomplete knowledge of the structure and function of the living cell. In narrowing this gap, minimal models of proteins have been developed as a step towards the goal of finding an “irreducible element” that still captures at least some of the essential physics and can reproduce and predict experimental measurements [1, 2]. All-atom models have been successful in folding small proteins [13, 14], elucidating the binding properties of small-molecule drugs [15], and characterizing complex molecular processes such as ribosomal translation [16]
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