Unfolding of titin domains studied by molecular dynamics simulations
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Titin, a ∼1 μm long protein found in striated muscle myofibrils, possesses unique elastic properties. The extensible behavior of titin has been demonstrated in atomic force microscopy and optical tweezer experiments to involve the reversible unfolding of individual immunoglobulin-like (Ig) domains. We have used steered molecular dynamics (SMD), a novel computer simulation method, to investigate the mechanical response of single titin Ig domains upon stress. Simulations of stretching Ig domains I1 and I27 have been performed in a solvent of explicit water molecules. The SMD approach provides a detailed structural and dynamic description of how Ig domains react to external forces. Validation of SMD results includes both qualitative and quantitative agreement with AFM recordings. Furthermore, combining SMD with single molecule experimental data leads to a comprehensive understanding of Ig domains' mechanical properties. A set of backbone hydrogen bonds that link the domains' terminal β-strands play a key role in the mechanical resistance to external forces. Slight differences in architecture permit a mechanical unfolding intermediate for I27, but not for I1. Refolding simulations of I27 demonstrate a locking mechanism.
KeywordsSteer Molecular Dynamic Atomic Force Microscopy Experiment Steer Molecular Dynamic Simulation Titin Domain Single Molecule Atomic Force Microscopy
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- Brünger AT (1992) X-PLOR, Version 3.1: A System for X-ray Crystallography and NMR. The Howard Hughes Medical Institute and Department of Molecular Biophysics and Biochemistry, Yale University.Google Scholar
- Freiburg A, Trombitas K, Hell W, Cazorla O, Fougerousse F, Centner T, Kolmerer B, Witt C, Beckmann J, Gregorio C, Granzier H and Labeit S (2000) Series of exon-skipping events in the elastic spring region of titin as the structural basis for myofibrillar elastic diversity. Circ Res 86: 1114-1121.PubMedGoogle Scholar
- Li H, Mariano CV, Oberhauser AF, Marszalek PE and Fernandez JM (2001a) Point mutations alter the mechanical stability of immunoglobulin modules. Nature Struct Biol 7: 1117-1120.Google Scholar
- LuH, Isralewitz B, Krammer A, Vogel V and Schulten K (1998) Unfolding of titin immunoglobulin domains by steered molecular dynamics simulation. Biophys J 75: 662-671.Google Scholar
- MacKerell Jr. AD, Bashford D, Bellott M, Dunbrack Jr. RL, Evanseck J, Field MJ, Fischer S, Gao J, Guo H, Ha S, Joseph D, Kuchnir L, Kuczera K, Lau FTK, Mattos C, Michnick S, Ngo T, Nguyen DT, Prodhom B, Reiher IWE, Roux B, Schlenkrich M, Smith J, Stote R, Straub J, Watanabe M, Wiorkiewicz-Kuczera J, Yin D and Karplus M (1998) All-hydrogen empirical potential for molecular modeling and dynamics studies of proteins using the CHARMM22 force field. J Phys Chem B 102: 3586-3616.CrossRefGoogle Scholar
- Schulten K, Schulten Z and Szabo A (1980) Reactions governed by a binomial redistribution process. The ehrenfest urn problem. Physica 100A: 599-614.Google Scholar
- Soteriou A, Clarke A, Martin S and Trinick J (1993) Titin folding energy and elasticity. Proc R Soc Lond B (Biol. Sci.) 254: 83-86.Google Scholar
- Tskhovrebova L and Trinick J (2002) Role of titin in vertebrate striated muscle. Proc R Soc Lond B (Biol. Sci.) 357: 199-206.Google Scholar