Article

Hierarchies, multiple energy barriers, and robustness govern the fracture mechanics of alpha-helical and beta-sheet protein domains.

Laboratory for Atomistic and Molecular Mechanics, Department of Civil and Environmental Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 11/2007; 104(42):16410-5. DOI: 10.1073/pnas.0705759104
Source: PubMed

ABSTRACT The fundamental fracture mechanisms of biological protein materials remain largely unknown, in part, because of a lack of understanding of how individual protein building blocks respond to mechanical load. For instance, it remains controversial whether the free energy landscape of the unfolding behavior of proteins consists of multiple, discrete transition states or the location of the transition state changes continuously with the pulling velocity. This lack in understanding has thus far prevented us from developing predictive strength models of protein materials. Here, we report direct atomistic simulation that over four orders of magnitude in time scales of the unfolding behavior of alpha-helical (AH) and beta-sheet (BS) domains, the key building blocks of hair, hoof, and wool as well as spider silk, amyloids, and titin. We find that two discrete transition states corresponding to two fracture mechanisms exist. Whereas the unfolding mechanism at fast pulling rates is sequential rupture of individual hydrogen bonds (HBs), unfolding at slow pulling rates proceeds by simultaneous rupture of several HBs. We derive the hierarchical Bell model, a theory that explicitly considers the hierarchical architecture of proteins, providing a rigorous structure-property relationship. We exemplify our model in a study of AHs, and show that 3-4 parallel HBs per turn are favorable in light of the protein's mechanical and thermodynamical stability, in agreement with experimental findings that AHs feature 3.6 HBs per turn. Our results provide evidence that the molecular structure of AHs maximizes its robustness at minimal use of building materials.

1 Bookmark
 · 
95 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The bacterial mechanosensitive channel MscL, a small protein mainly activated by membrane tension, is a central model system to study the transduction of mechanical stimuli into chemical signals. Mutagenic studies suggest that MscL gating strongly depends on both intra-protein and interfacial lipid-protein interactions. However, there is a gap between this detailed chemical information and current mechanical models of MscL gating. Here, we investigate the MscL bilayer-protein interface through molecular dynamics simulations, and take a combined continuum-molecular approach to connect chemistry and mechanics. We quantify the effect of membrane tension on the forces acting on the surface of the channel, and identify interactions that may be critical in the force transduction between the membrane and MscL. We find that the local stress distribution on the protein surface is largely asymmetric, particularly under tension, with the cytoplasmic side showing significantly larger and more localized forces, which pull the protein radially outward. The molecular interactions that mediate this behavior arise from hydrogen bonds between the electronegative oxygens in the lipid headgroup and a cluster of positively charged lysine residues on the amphipathic S1 domain and the C-terminal end of the second trans-membrane helix. We take advantage of this strong interaction (estimated to be 10–13 kT per lipid) to actuate the channel (by applying forces on protein-bound lipids) and explore its sensitivity to the pulling magnitude and direction. We conclude by highlighting the simple motif that confers MscL with strong anchoring to the bilayer, and its presence in various integral membrane proteins including the human mechanosensitive channel K2P1 and bovine rhodopsin. OPEN ACCESS
    PLoS ONE 12/2014; 9(12):e113947. DOI:10.1371/journal.pone.0113947 · 3.53 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Single-molecule dynamic force spectroscopy (DFS) is a powerful tool for studying mechanical forces of molecular interactions. Recently, the important role of bond rebinding in DSF experiments was recognized, which intrigued mounting researches in this direction. In this work, we study how the bond rebinding influences the strength of single-molecular bonds using Brownian dynamics (BD) simulations and theoretical modeling. Our results show that bond rebinding significantly enhances the strength of single-molecular bond at ultralow loading rates. The rebinding behavior strongly depends on the loading stiffness, suggesting that the strength of single-molecular bond is not only dependent on its intrinsic property, but also the stiffness of loading device. By connecting our new model with conventional theories that did not consider the rebinding effect and are only applied to high loading rates, we propose a unified scheme to predict the rupture forces in a full range of loading rate in DSF experiments and simulations.
    International Journal of Applied Mechanics 02/2015; 7(1):1550015. DOI:10.1142/S1758825115400153 · 1.29 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Poly-L-glutamic acid (PGA) is a widely used biomaterial, with applications ranging from drug delivery and biological glues to food products and as a tissue engineering scaffold. A biodegradable material with flexible conjugation functional groups, tunable secondary structure and mechanical properties, PGA has potential as a tunable matrix material in mechanobiology. Recent studies in proteins connecting dynamics, nanometer length scale rigidity, and secondary structure suggest a new point of view from which to analyze and develop this promising material. We have characterized the structure, topology, and rigidity properties of PGA prepared with different molecular weights and secondary structures through various techniques including SEM, FT-IR, light and neutron scattering spectroscopy. On the length scale of a few nanometers rigidity is determined by hydrogen bonding interactions in presence of neutral species and by electrostatic interactions when the polypeptide is negatively charged. When probed over hundreds of nanometers, the rigidity of these materials is modified by long range intermolecular interactions that are introduced by the supramolecular structure. This article is protected by copyright. All rights reserved. Copyright © 2015 Wiley Periodicals, Inc., A Wiley Company.
    Journal of Biomedical Materials Research Part A 02/2015; DOI:10.1002/jbm.a.35427 · 2.83 Impact Factor

Full-text (2 Sources)

Download
15 Downloads
Available from
Jul 4, 2014