TCB Publications - Abstract

Mu Gao, Matthias Wilmanns, and Klaus Schulten. Steered molecular dynamics studies of titin I1 domain unfolding. Biophysical Journal, 83:3435-3445, 2002. (PMC: 1302418)

GAO2002 The cardiac muscle protein titin, responsible for developing passive elasticity and extensibility of muscle, possesses about 40 immunoglobulin-like (Ig) domains in its I band region. Atomic force microscopy and steered molecular dynamics (SMD) have been successfully combined to investigate the reversible unfolding of individual Ig domains. However, previous SMD studies of titin I-band modules have been restricted to I27, the only structurally known Ig domain from the distal region of the titin I-band. In this paper we report SMD simulations unfolding I1, the first structurally available Ig domain from the proximal region of the titin I band. The simulations are carried out with a view towards upcoming atomic force microscopy experiments. Both constant velocity and constant force stretching have been employed to model mechanical unfolding of oxidized I1, which has a disulfide bond bridging $\beta$-strands C and E, as well as reduced I1 in which the disulfide bridge is absent. The simulations reveal that I1 is protected against external stress mainly through six inter-strand hydrogen bonds between its A and B $\beta$-strands. The disulfide bond enhances the mechanical stability of oxidized I1 domains by restricting the rupture of backbone hydrogen bonds between the A'- and G-strands. The disulfide bond also limits the maximum extension of I1 to $\sim$220 Å. Comparison of the unfolding pathways of I1 and I27 are provided and implications to AFM experiments are discussed.

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