Rafael C. Bernardi, Ellis Durner, Constantin Schoeler, Klara H. Malinowska,
Bruna G. Carvalho, Edward A. Bayer, Zaida Luthey-Schulten, Hermann E. Gaub,
and Michael A. Nash.
Mechanisms of nanonewton mechanostability in a protein complex
revealed by molecular dynamics simulations and single-molecule force
spectroscopy.
Journal of the American Chemical Society, 141:14752-14763,
2019.
(PMC: PMC6939381)
BERN2019-ZLS
Can molecular dynamics simulations predict the mechanical behavior of protein
complexes?
Can simulations decipher the role of protein domains of unknown function in
large
macromolecular complexes? Here, we employ a wide-sampling computational
approach to
demonstrate that molecular dynamics simulations, when carefully performed
and combined
with single-molecule atomic force spectroscopy experiments, can predict and
explain the
behavior of highly mechanostable protein complexes. As a test case, we studied
a previously
unreported homologue from Ruminococcus flavefaciens called X-module-
Dockerin (XDoc)
bound to its partner Cohesin (Coh). By performing dozens of short simulation
replicas near
the rupture event, and analyzing dynamic network fluctuations, we were able to
generate
large simulation statistics and directly compare them with experiments to
uncover the
mechanisms involved in mechanical stabilization. Our single-molecule force
spectroscopy
experiments show that the XDoc-Coh homologue complex withstands forces up
to 1 nN at
loading rates of pN/s. Our simulation results reveal that this remarkable
mechanical
stability is achieved by a protein architecture that directs molecular deformation
along paths
that run perpendicular to the pulling axis. The X-module was found to play a
crucial role in
shielding the adjacent protein complex from mechanical rupture. These
mechanisms of
protein mechanical stabilization have potential applications in biotechnology for
the
development of systems exhibiting shear enhanced adhesion or tunable
mechanics.
pN/s. Our simulation results reveal that this remarkable
mechanical
stability is achieved by a protein architecture that directs molecular deformation
along paths
that run perpendicular to the pulling axis. The X-module was found to play a
crucial role in
shielding the adjacent protein complex from mechanical rupture. These
mechanisms of
protein mechanical stabilization have potential applications in biotechnology for
the
development of systems exhibiting shear enhanced adhesion or tunable
mechanics.
