Actin is a highly abundant protein that has a conserved structure across many species. It occurs in a monomer and polymer form and is involved in cell motility, division, organelle transport and muscle contraction. Actin binds to adenosine triphosphate (ATP) and will also catalyze its hydrolysis to adenosine diphosphate (ADP). The rates for this reaction are greatly different for free actin monomers and polymerized actin monomers. Additionally, the state of this nucleotide - ATP, ADP, or ADP plus an inorganic phosphate - plays a critical role in the structure, function and dynamics of actin. Despite experimental and computational scrutiny, there remain many questions about the effect of the bound nucleotide on actin polymers as well as the mechanism of actin catalyzed-ATP hydrolysis. In addition to its role in actin function, the hydrolysis of ATP to ADP is also the main source of energy used to drive biological reactions. Due to its importance to biochemistry, the exact nature of the source of this energy in different environments (protein and solution) remains an area of active debate. Our knowledge in these areas can be improved through the development, application and eventual combination of two different molecular dynamics (MD) methods. The main benefit of MD simulations is that they contain the atomistic details of the problem of interest but they suffer from their inability to allow bonds to break and reform. However, a reactive MD simulation of ATP hydrolysis can be constructed via the proposed multistate molecular dynamics (MS-MD) methodology. MS-MD is a generalization of the multistate empirical valence bond (MS-EVB) theory, which has hitherto been mainly applied to proton solvation and transport in water and has been recently extended to amino acid protonation. However, atomistic MD is computationally expensive for large systems like polymerized actin. This bottleneck can be overcome if some or all of the actin polymer is treated with a simplified, coarse-grained (CG) model using the multiscale coarse-graining (MS-CG) scheme, which is derived from the interactions of the full, atomistic-scale model. The combination of MS-MD and MS-CG will allow for the first detailed, accurate, fully reactive MD simulations of the nucleotide related properties of actin including actin-catalyzed ATP hydrolysis.
Actin is a key protein involved in cell division. Thus, it has been utilized as a target for cancer drugs. Additionally, since actin is also a structural protein involved in muscle contraction, its mutations are linked to several genetic muscle myopathies. Thus, understanding the detailed behavior of actin can allow for a more rational design of drugs and preventative agents for the above actin related diseases.