TCB Publications - Abstract

Hui Lu and Klaus Schulten. The key event in force-induced unfolding of titin's immunoglobulin domains. Biophysical Journal, 79:51-65, 2000. (PMC: 1300915)

LU2000 Steered molecular dynamics simulation of force-induced titin immunoglobulin domain I27 unfolding led to the discovery of a significant potential energy barrier at an extension of about 14 Å on the unfolding pathway that protects the domain against stretching. Previous simulations showed that this barrier is due to the concurrent breaking of six interstrand hydrogen bonds (H-bonds) between $\beta$-strands A$^\prime$ and G that is preceded by the breaking of two to three hydrogen bonds between strands A and B leading to an unfolding intermediate. The simulation results is supported by -resolution atomic force microscopy data. Here we perform a structural and energetic analysis of the H-bonds breaking. It is confirmed that H-bonds between strands A and B break rapidly. However, the breaking of the H-bonds between strands A' and G needs to be assisted by fluctuations of water molecules. In nanosecond simulations, water molecules are found to repeatedly interact with the protein backbone atoms, weakening individual interstrand H-bonds until all six A$^\prime$-G H-bonds break simultaneously under the influence of external stretching forces. Only when those bonds are broken can the generic unfolding take place, which involves hydrophobic interactions of the protein core and exerts weaker resistance against stretching than the key event.

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