Biomolecular Dynamics of Force Generation and Movement in Muscle

Professor David Thomas and his coworkers in the Department of Biochemistry of the Medical School are using supercomputers to study the molecular mechanism of muscle contraction. Thomas and his group augment their experimental work by performing computation and molecular dynamics simulations on super-computers in order to develop more complete and accurate models of force generation and movement in muscle.

The molecular motor for muscular movement involves the direct interaction of myosin and actin coupled to the hydrolysis of ATP. The experimental work relies on the use of spectroscopic probes, which are attached to the myosin head. These spectroscopic probes can then be analyzed to provide data describing the molecular motion of myosin and actin. The spectroscopic probes are analyzed optically, through the use of lasers and fluorescent and phosphorescent dyes; and also through the use of magnetic resonance (microwave), which is more sensitive to angular motion. Supercomputer research allows efficient evaluation of molecular models based on whether they correspond to the observed spectroscopy data.

A recent discovery by the Thomas group is that the myosin heads in contracting fibers were found to be dynamicallly disordered and to exhibit Brownian motion rather than existing in a distinct 90deg. orientation to the actin molecule. This irregular movement is not consistent with the classical model for force generation in which heads undergo a 45deg. transition between two distinct orientations.

This finding has led these researchers to propose that force is produced by a disorder-to-order transition in which myosin heads bind initially to actin in a dynamically disordered state, and through the hydrolysis of ATP, they increase their affinity to actin and assume a rigor like (45deg.) orientation (see figure below).

Thomas's work is funded in part by the National Institutes of Health, the Muscular Dystrophy Association, and the National Heart Association. His researchers are undergraduate, medical, and graduate students, and post-doctoral fellows associated with the Biochemistry, Biophysical Sciences, Physics, Neuroscience and Scientific Computation programs at the University of Minnesota.

For a more detailed discussion of this research, please refer to the following publications:

E. C. Howard, K.M. Lindahl, C. F. Polnaszek, and D. D. Thomas.
Simulation of Saturation Transfer EPR Spectra for Rotational Motion with Restricted Angular Amplitude. Biophys. J. 64 (1993) 581-593.

J. C. Voss, L. R. Jones, and D. D. Thomas.
The Physical Mechanism of Calcium Pump Regulation in the Heart. Biophys. J. 67 (1994) 190-196.

D. D. Thomas, S. Ramachandran, O. Roopnarine, D. W. Hayden, and E. M. Ostap.
The Mechanism of Force Generation in Myosin: A Disorder-to-Order Transition, Coupled to Internal Structural Changes. Biophys. J. 68 (1995) 135s-141s. (This article is also listed in the UMSI series as UMSI 95/70R).

O. Roopnarine and D. D. Thomas.
Orientational Dynamics of Indane Dione Spin-Labeled Myosin Head in Relaxed and Contracting Skeletal Muscle Fibers. Biophys. J. 68 (1995) 1461-1471. (This article is also listed in the UMSI series as UMSI 95/69R).

E. M. Ostap, V. A. Barnet, and D. D. Thomas.
Resolution of Three Structural States of Spin-Labeled Myosin in Contracting Muscle. Biophys. J. (in press).