Research Topics - Steered/Interactive Molecular Dynamics

Knowledge of the mechanism of association, dissociation and unfolding of macromolecules is important for many biological processes. Among the examples are the binding and dissociation of substrates of enzyme reactions, the recognition of ligands by their receptors or the elastic resopnse of mechanical proteins. In order to study such processes external forces can be applied reducing energy barriers and therefore increasing the probability of unlikely events on the time scale of molecular dynamics. This approach has the advantage that it corresponds closely to micromanipulation through atomic force microscopy or optical tweezers. The external force techniques can be applied to study many processes, including dissociation of avidin-biotin complex, dissociation of retinal from bacteriorhodopsin, stretching of titin, etc. The molecular dynamics program NAMD, developed in the group, is capable of performing several different kinds of SMD, including rotation or translation of one or more atoms. The group's molecular graphics program VMD provides a powerful means of visualizing these simulations, and through the Interactive Molecular Dynamics (IMD) interface can even allow SMD simulations to be performed in real time.

Titin Z1Z2-Telethonin Complex

image size: 301.5KB
made with VMD

Muscle fibers are not rigid structures, but rather, they can both contract and extend in response to physiological demand. As a result, muscle sarcomeres must have a protective mechanism to prevent tearing and damage from overstretching. The giant protein titin fulfills this role by acting as a molecular rubber band, providing a passive resistance force during extension to restore the muscle fiber to its resting length. Conceivably, this rubber band must be anchored to a rigid structure in order to function. Biochemical investigations have speculated that the protein telethonin, located at the sarcomeric Z-disc, may serve this purpose. Genetic diseases related to defects in telethonin have been correlated with dilated cardiomyopathy and a form of muscular dystrophy. To date there have been no studies to determine how strongly bound titin is to telethonin. To explore this issue, we performed molecular dynamics simulations in order to test the strength of the newly resolved titin Z1Z2-telethonin complex. Our results, which have recently been reported (paper), reveal that the force required to dissociate titin from telethonin is significantly higher than that required to unfold isolated titin Ig-domains. This suggests strongly that telethonin is in fact an essential component of the Z-disc titin anchor. In addition, we find that telethonin anchors not just one, but two separate titin molecules, serving as a sort of molecular glue joining both titin molecules together through β-strand crosslinking (a structural motif also seen in fibril pathologies such as Alzheimer's, Parkinson, and Huntington's disease). Thus our simulations reveal also a fundamental architectural element of living cells, namely how cells glues their components together yielding strong mechanical connections. For more information on teletonin and the implications of our findings, see the following webpage here.

All Spotlights


Onset of anthrax toxin pore formation. Mu Gao and Klaus Schulten. Biophysical Journal, 90:3267-3279, 2006.

What makes an aquaporin a glycerol channel: A comparative study of AqpZ and GlpF. Yi Wang, Klaus Schulten, and Emad Tajkhorshid. Structure, 13:1107-1118, 2005.

In search of the hair-cell gating spring: Elastic properties of ankyrin and cadherin repeats. Marcos Sotomayor, David P. Corey, and Klaus Schulten. Structure, 13:669-682, 2005.

Calculating potentials of mean force from steered molecular dynamics simulations. Sanghyun Park and Klaus Schulten. Journal of Chemical Physics, 120:5946-5961, 2004.

Insights into the molecular mechanism of rotation in the Fo sector of ATP synthase. Aleksij Aksimentiev, Ilya A. Balabin, Robert H. Fillingame, and Klaus Schulten. Biophysical Journal, 86:1332-1344, 2004.

Mechanisms of selectivity in channels and enzymes studied with interactive molecular dynamics. Paul Grayson, Emad Tajkhorshid, and Klaus Schulten. Biophysical Journal, 85:36-48, 2003.

Identifying unfolding intermediates of FN-III10 by steered molecular dynamics. Mu Gao, David Craig, Viola Vogel, and Klaus Schulten. Journal of Molecular Biology, 323:939-950, 2002.

Structural determinants of MscL gating studied by molecular dynamics simulations. Justin Gullingsrud, Dorina Kosztin, and Klaus Schulten. Biophysical Journal, 80:2074-2081, 2001.

Unfolding of titin immunoglobulin domains by steered molecular dynamics simulation. Hui Lu, Barry Isralewitz, André Krammer, Viola Vogel, and Klaus Schulten. Biophysical Journal, 75:662-671, 1998.

Molecular dynamics study of unbinding of the avidin-biotin complex. Sergei Izrailev, Sergey Stepaniants, Manel Balsera, Yoshi Oono, and Klaus Schulten. Biophysical Journal, 72:1568-1581, 1997.