Multiscale modeling of structural dynamics underlying force generation and product release in actomyosin complex

Area of Science:

• Biophysics
• Molecular Biology
• Computational Biology

Background:

• Understanding myosin motor function is key to deciphering muscle contraction mechanisms.
• High-resolution insights into actomyosin conformational changes are needed.

Purpose of the Study:

• To computationally model the allosteric couplings and transition pathway of the actomyosin complex.
• To elucidate the structural basis of force generation and product release in myosin.

Main Methods:

• Multiscale modeling combining coarse-grained and all-atom molecular dynamics simulations.
• Analysis of pre-powerstroke and post-powerstroke states, and the transition pathway.
• Atomistic simulations of active-site dynamics.

Main Results:

• Identified key actin-activated couplings critical for force generation and sequential product release.
• Revealed isoform-dependent couplings in Myosin II and Myosin V.
• Detailed the structural events during the powerstroke, including phosphate and ADP release.
• Showed weakened phosphate coordination and disrupted salt bridges in the transition state, favoring phosphate release before MgADP.

Conclusions:

• The study provides a detailed mechanistic understanding of myosin motor function.
• Offers insights into the controversy surrounding actin-activated phosphate release and force generation.
• Highlights the importance of multiscale modeling in studying complex molecular machines.