Key result
In silico molecular dynamics simulations of actin-myosin binding showed that enthalpy provides basal binding affinity, while entropy enhances it at higher temperatures.
This coarse-grained simulation elucidates the thermodynamic mechanisms of actin-myosin binding, showing how enthalpy and entropy coexist to drive protein association.
Does not alter clinical management; leaves open validation of temperature-dependent actin-myosin thermodynamics in cardiac models.
Association of protein molecules constitutes the basis for the interaction network in a cell. Despite its fundamental importance, the thermodynamic aspect of protein-protein binding, particularly the issues relating to the entropy change upon binding, remains elusive. The binding of actin and myosin, which are vital proteins in motility, is a typical example, in which two different binding mechanisms have been argued: the binding affinity increases with increasing temperature and with decreasing salt-concentration, indicating the entropy-driven binding and the enthalpy-driven binding, respectively. How can these thermodynamically different binding mechanisms coexist? To address this question, which is of general importance in understanding protein-protein bindings, we conducted an in silico titration of the actin-myosin system by molecular dynamics simulation using a residue-level coarse-grained model, with particular focus on the role of the electrostatic interaction. We found a good agreement between in silico and in vitro experiments on the salt-concentration dependence and the temperature dependence of the binding affinity. We then figured out how the two binding mechanisms can coexist: the enthalpy (due to electrostatic interaction between actin and myosin) provides the basal binding affinity, and the entropy (due to the orientational disorder of water molecules) enhances it at higher temperatures. In addition, we analyzed the actin-myosin complex structures observed during the simulation and obtained a variety of weak-binding complex structures, among which were found an unusual binding mode suggested by an earlier experiment and precursor structures of the strong-binding complex proposed by electron microscopy. These results collectively indicate the potential capability of a residue-level coarse-grained model to simulate the association-dissociation dynamics (particularly for transient weak-bindings) exhibited by larger and more complicated systems, as in a cell.
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Okazaki et al. (2012) studied Protein-protein binding (actin-myosin interaction). In silico titration by molecular dynamics simulation was evaluated on Binding affinity dependence on salt-concentration and temperature. In silico molecular dynamics simulations of actin-myosin binding showed that enthalpy provides basal binding affinity, while entropy enhances it at higher temperatures.
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