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Biophys J, July 2000, p. 51-65, Vol. 79, No. 1
*Beckman Institute for Advanced Science and Technology and
Department of Physics University of Illinois at Urbana-Champaign,
Urbana, Illinois 61801 USA
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 ~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 
-strands A' and
G that is preceded by the breaking of two to three hydrogen bonds
between strands A and B, the latter leading to an unfolding intermediate. The simulation results are supported by
Ångstrom-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-bond 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'-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.
Biophys J, July 2000, p. 51-65, Vol. 79, No. 1
© 2000 by the Biophysical Society 0006-3495/00/07/51/15 $2.00
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