Titin, a 1(m-long protein (7,800 atoms) found in striated muscle myofibrils, possesses unique elastic and extensibility properties in its I-band region, which is largely composed of a PEVK region and 7-strand (-sandwich immunoglobulin-like (Ig) domains [50]. The behavior of titin as a multi-stage entropic spring has been shown in atomic force microscopy [54] and optical tweezer experiments to partially depend on the reversible unfolding of individual Ig domains. We performed SMD simulations* to stretch single titin Ig domains in solution with pulling speeds of 0.5 and 1.0E/ps [7]. The resulting force-extension profiles exhibit a single dominant peak for each Ig domain unfolding, consistent with the experimentally observed sequential, as opposed to concerted, unfolding of Ig domains under external stretching forces. This force peak can be attributed to an initial burst of backbone hydrogen bonds, which takes place between anti-parallel (-strands A and B and between paral lel (-strands A' and G. Additional features of the simulations, including the position of the force peak and relative unfolding resistance of different Ig domains, can be related to experimental observations. Similar elastic behavior is also found in other protein domains, such as tenascin fibronectin-III-like domains. Simulations of fibronectin-III domain unfolding, and of unfolding of two connected Ig domains, are currently ongoing.
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