This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Titin is a mechanical protein ( protects muscle from overstretching, which can occur following a powerful musclecontraction. Defects in the titin gene have been correlated to muscular distrophy.Titin produces a restoring force when a muscle fiber is extended beyond its normallength. Much of what is understood about titin today arose from single-moleculeexperiments [1?7] and computer simulations [8?13] which have shed light on howthe structure of titin resist mechanical stretching forces.The task of connecting observations in simulations to observations in experiments,however, have been limited by the cost for performing calculations that match thetimescale of experiments. As a result, simulations have often focused on biologicalevents that take place at very fast timescales that are outside the range of observationby experiments. This project has addressed this concern by improving the performance of simulations such that they have closed the time scale gap betweensimulation and experiment.Bibliography[1] M. Rief, M. Gautel, F. Oesterhelt, J. M. Fernandez, and H. E. Gaub. Reversibleunfolding of individual titin immunoglobulin domains by AFM. Science, 276:1109?1112, 1997.[2] M. Carrion-Vazquez, A. Oberhauser, S. Fowler, P. Marszalek, S. Broedel, J. Clarke,and J. Fernandez. Mechanical and chemical unfolding of a single protein: A comparison.Proc. Natl. Acad. Sci. USA, 96:3694?3699, 1999.[3] P. E. Marszalek, H. Lu, H. Li, M. Carrion-Vazquez, A. F. Oberhauser, K. Schulten,and J. M. Fernandez. Mechanical unfolding intermediates in titin modules. Nature,402:100?103, 1999.[4] H. Li, W. Linke, A. F. Oberhauser, M. Carrion-Vazquez, J. G. Kerkvliet, H. Lu, P. E.Marszalek, and J. M. Fernandez. Reverse engineering of the giant muscle proteintitin. Nature, 418:998?1002, 2002.[5] S. B. Fowler, R. B. Best, J. L. T. Herrera, T. J. Rutherford, A. Steward, E. Paci,M. Karplus, and J. Clarke. Mechanical unfolding of a titin Ig domain: Structure ofunfolding intermediate revealed by combining AFM, molecular dynamics simulations,NMR and protein engineering. J. Mol. Biol., 322:841?849, 2002.[6] H. B. Li and J. M. Fernandez. Mechanical design of the first proximal Ig domainof human cardiac titin revealed by single molecule force spectroscopy. J. Mol. Biol.,334:75?86, 2003.[7] P. M. Williams, S. B. Fowler, R. B. Best, J. L. Toca-Herrera, K. A. Scott, A. Steward,and J. Clarke. Hidden complexity in the mechanical properties of titin. Nature,422:446?449, 2003.[8] H. Lu, B. Isralewitz, A. Krammer, V. Vogel, and K. Schulten. Unfolding of titinimmunoglobulin domains by steered molecular dynamics simulation. Biophys. J.,75:662?671, 1998.[9] H. Lu and K. Schulten. Steered molecular dynamics simulations of force-inducedprotein domain unfolding. Proteins: Struct., Func., Gen., 35:453?463, 1999.[10] H. Lu and K. Schulten. The key event in force-induced unfolding of titin's immunoglobulindomains. Biophys. J., 79:51?65, 2000.[11] M. Gao, H. Lu, and K. Schulten. Simulated refolding of stretched titin immunoglobulindomains. Biophys. J., 81:2268?2277, 2001.[12] M. Gao, H. Lu, and K. Schulten. Unfolding of titin domains studied by moleculardynamics simulations. J. Muscle Res. Cell Mot., 23:513?521, 2002.[13] R. B. Best, S. B. Fowler, J. L. T. Herrera, A. Steward, E. Paci, and J. Clarke.Mechanical unfolding of a titin Ig domain: Structure of transition state revealedby combining atomic force microscopy, protein engineering and molecular dynamicssimulations. J. Mol. Biol., 330:867?877, 2003.

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