Molecular dynamics simulation of a myosin subfragment-1 docking with an actin filament

Myosins are typical molecular motor proteins, which convert the chemical energy of ATP into mechanical work. The fundamental mechanism of this energy conversion is still unknown. To explain the experimental results observed in molecular motors, Masuda has proposed a theory called the "Driven by Detachment (DbD)" mechanism for the working principle of myosins. Based on this theory, the energy used during the power stroke of the myosins originates from the attractive force between a detached myosin head and an actin filament, and does not directly arise from the energy of ATP. According to this theory, every step in the myosin working process may be reproduced by molecular dynamics (MD) simulations, except for the ATP hydrolysis step. Therefore, MD simulations were conducted to reproduce the docking process of a myosin subfragment-1 (S1) against an actin filament. A myosin S1 directed toward the barbed end of an actin filament was placed at three different positions by shifting it away from the filament axis. After 30 ns of MD simulations, in three cases out of ten trials on average, the myosin made a close contact with two actin monomers by changing the positions and the orientation of both the myosin and the actin as predicted in previous studies. Once the docking was achieved, the distance between the myosin and the actin showed smaller fluctuations, indicating that the docking is stable over time. If the docking was not achieved, the myosin moved randomly around the initial position or moved away from the actin filament. MD simulations thus successfully reproduced the docking of a myosin S1 with an actin filament. By extending the similar MD simulations to the other steps of the myosin working process, the validity of the DbD theory may be computationally demonstrated.

[1]  Michael A. Geeves,et al.  Molecular motors: Stretching the lever-arm theory , 2002, Nature.

[2]  D A Winkelmann,et al.  Three-dimensional structure of myosin subfragment-1: a molecular motor. , 1993, Science.

[3]  Mitsunori Takano,et al.  Unidirectional Brownian motion observed in an in silico single molecule experiment of an actomyosin motor , 2010, Proceedings of the National Academy of Sciences.

[4]  J. Berg,et al.  A millennial myosin census. , 2001, Molecular biology of the cell.

[5]  E Pirozzi,et al.  On Myosin II dynamics in the presence of external loads. , 2005, Bio Systems.

[6]  K C Holmes,et al.  Structural mechanism of muscle contraction. , 1999, Annual review of biochemistry.

[7]  Toshio Yanagida,et al.  Cooperative actions between myosin heads bring effective functions , 2007, Biosyst..

[8]  Carl A. Morris,et al.  The structure of the myosin VI motor reveals the mechanism of directionality reversal , 2005, Nature.

[9]  Gerrit Groenhof,et al.  GROMACS: Fast, flexible, and free , 2005, J. Comput. Chem..

[10]  Hiroto Tanaka,et al.  Simultaneous Observation of Individual ATPase and Mechanical Events by a Single Myosin Molecule during Interaction with Actin , 1998, Cell.

[11]  N. Okimoto,et al.  Theoretical studies of the ATP hydrolysis mechanism of myosin. , 2001, Biophysical journal.

[12]  Andrij Baumketner,et al.  Early stages of the recovery stroke in myosin II studied by molecular dynamics simulations , 2011, Protein science : a publication of the Protein Society.

[13]  Toshio Yanagida,et al.  Single molecule processes on the stepwise movement of ATP-driven molecular motors. , 2003, Bio Systems.

[14]  Toshio Yanagida,et al.  Sliding distance of actin filament induced by a myosin crossbridge during one ATP hydrolysis cycle , 1985, Nature.

[15]  S Sato,et al.  A chemically driven fluctuating ratchet model for actomyosin interaction. , 2003, Bio Systems.

[16]  Tadashi Masuda.  A deterministic mechanism producing the loose coupling phenomenon observed in an actomyosin system , 2009, Biosyst..

[17]  M. Schliwa.  Myosin steps backwards , 1999, Nature.

[18]  Carsten Kutzner,et al.  GROMACS 4:  Algorithms for Highly Efficient, Load-Balanced, and Scalable Molecular Simulation. , 2008, Journal of chemical theory and computation.

[19]  D. Manstein,et al.  Molecular engineering of a backwards-moving myosin motor , 2004, Nature.

[20]  K Schulten,et al.  VMD: visual molecular dynamics. , 1996, Journal of molecular graphics.

[21]  Daniel Safer,et al.  Myosin VI is an actin-based motor that moves backwards , 1999, Nature.

[22]  W. Kabsch,et al.  Atomic structure of the actin: DNase I complex , 1990, Nature.

[23]  Tadashi Masuda.  An electromechanical model of myosin molecular motors. , 2003, Journal of theoretical biology.

[24]  Hanspeter Winkler,et al.  Molecular modeling of averaged rigor crossbridges from tomograms of insect flight muscle. , 2002, Journal of structural biology.

[25]  R A Milligan,et al.  Protein-protein interactions in the rigor actomyosin complex. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[26]  Tadashi Masuda,et al.  A possible mechanism for determining the directionality of myosin molecular motors , 2008, Biosyst..