Mechanisms of Nanonewton Mechanostability in a Protein Complex Revealed by Molecular Dynamics Simulations and Single-Molecule Force Spectroscopy

Rafael C. Bernardi, Ellis Durner, Constantin Schoeler, Klara H. Malinowska, Bruna G. Carvalho, Edward A. Bayer, Zaida Luthey-Schulten, Hermann E. Gaub, Michael A. Nash

Research output: Contribution to journalArticle

Abstract

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 105 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.

Original languageEnglish (US)
Pages (from-to)14752-14763
Number of pages12
JournalJournal of the American Chemical Society
Volume141
Issue number37
DOIs
StatePublished - Sep 18 2019

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Molecular Dynamics Simulation
Molecular dynamics
spectroscopy
Spectroscopy
Proteins
Molecules
protein
Computer simulation
simulation
Rupture
Ruminococcus
rupture
stabilization
Macromolecular Substances
Stabilization
Biotechnology
Mechanics
Mechanical stability
experiment
Experiments

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

Mechanisms of Nanonewton Mechanostability in a Protein Complex Revealed by Molecular Dynamics Simulations and Single-Molecule Force Spectroscopy. / Bernardi, Rafael C.; Durner, Ellis; Schoeler, Constantin; Malinowska, Klara H.; Carvalho, Bruna G.; Bayer, Edward A.; Luthey-Schulten, Zaida; Gaub, Hermann E.; Nash, Michael A.

In: Journal of the American Chemical Society, Vol. 141, No. 37, 18.09.2019, p. 14752-14763.

Research output: Contribution to journalArticle

Bernardi, Rafael C. ; Durner, Ellis ; Schoeler, Constantin ; Malinowska, Klara H. ; Carvalho, Bruna G. ; Bayer, Edward A. ; Luthey-Schulten, Zaida ; Gaub, Hermann E. ; Nash, Michael A. / Mechanisms of Nanonewton Mechanostability in a Protein Complex Revealed by Molecular Dynamics Simulations and Single-Molecule Force Spectroscopy. In: Journal of the American Chemical Society. 2019 ; Vol. 141, No. 37. pp. 14752-14763.
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