Computer Modeling of Force-Induced Titin Domain Unfolding
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Titin, a 1 μm long protein found in striated muscle myofibrils, possesses unique elastic and extensibility properties, and is largely composed of a PEVK region and β-sandwich immunoglobulin (Ig) and fibronectin type III (FnIII) domains. The extensibility behavior of titin has been shown in atomic force microscope and optical tweezer experiments to partially depend on the reversible unfolding of individual Ig and Fnlll domains. We performed steered molecular dynamics simulations to stretch single titin Ig domains in solution with pulling speeds of 0.1 – 1.0 Å/ps, and Fnlll domains with a pulling speed of 0.5 Å/ps. Resulting force-extension profiles exhibit a single dominant peak for each domain unfolding, consistent with the experimentally observed sequential, as opposed to concerted, unfolding of Ig and Fnlll domains under external stretching forces. The force peaks can be attributed to an initial burst of a set of backbone hydrogen bonds connected to the domains’ terminal β-strands. Constant force stretching simulations, applying 500 – 1000 pN of force, were performed on Ig domains. The resulting domain extensions are halted at an initial extension of 10 Å until the set of all six hydrogen bonds connecting terminal β-strands break simultaneously. This behavior is accounted for by a barrier separating folded and unfolded states, the shape of which is consistent with AFM and chemical denaturation data.
KeywordsAtomic Force Microscopy Rupture Force Atomic Force Microscopy Data Atomic Force Microscopy Experiment Steer Molecular Dynamics Simulation
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