Discovering How Muscles Really Work
Key Challenges: Using simulation to understand the fundamental basis for the conversion of the chemical energy resulting from metabolism to mechanical work done by cells in the body. A central focus is on the role of ATP, the biological fuel that is synthesized and utilized during muscle movement. The differential binding of ATP and its hydrolysis products induce protein conformational changes that result in motion but many questions about the precise mechanism exist. A variety of simulation types are required, including restrained targeted molecular dynamics, multicopy enhanced sampling (MCES) methods, “string method” molecular dynamics (used to find minimum energy pathways connecting two metastable states of a system), and classical molecular dynamics in combination with polymer theory.
Why it Matters: The focus of this work is increased understanding of the function of living cells, especially a group of proteins called Myosins. Myosins generate force and movement in skeletal muscle but the atomic details of the force-generating `powerstroke' remain poorly understood. An understanding of the interconversion between ATP and mechanical work is essential for developing precise control in a variety of microscopic systems of importance in biotechnology solutions for energy and the environment. This includes photosynthetic membranes, ethanol fermentation in bacterial systems, and engineered microorganisms for bio-powered separation, purification, or assembly of materials. Results from this work are expected to aid in modifying the systems studied to make them useful in the biological production of energy, as well as in the utilization of energy by molecular motors (nanoscale machines made of proteins) to perform useful mechanical work.
Accomplishments: Myosin motor function depends on the interaction between different domains within the protein that transmit information from one part of the molecule to another. Simulations using NERSC and other resources have analyzed conformation changes and interdomain coupling in the myosin V and VI molecules. These simulations reveal the mechanical coupling pathways, the key hydrogen bond ruptures involved, the transition paths, the free energies along the paths, and the rates of interconversion. They also explain the step size variability of myosin VI that has been observed in experiments, and suggest key residues for experimental testing. The myosin V simulation, which treated the entire motor domain, represents the first all-atom RTMD investigation of this molecule and this study was carried out entirely at NERSC. The methodology developed for these studies is expected to be useful more generally in studies of conformational transitions in complex biomolecules.
Investigators: Professor Martin Karplus (Harvard) leads this work. In 1977 Professor Karplus published the first molecular dynamics simulation of a protein.
NERSC Role: NERSC provides the major part of the computer resources used by the Karplus laboratory. In addition, NERSC is the primary facility used during development and testing of parallel CHARMM, the widely used set of force fields and molecular dynamics simulation and analysis software developed and maintained by the Karplus group. Considerable NERSC storage resources are also required to archive MD simulation trajectories generated by the String Methods, QM/MM, and direct MD calculations.
More Information: See, for example, Journal of Molecular Biology, 395(4), (2010); Journal of Chemical Physics, 134, 085103 (2011); and Professor Karplus' web site.