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Unraveling the mystery of ATP hydrolysis in actin filaments.

ABSTRACT: Actin performs its myriad cellular functions by the growth and disassembly of its filamentous form. The hydrolysis of ATP in the actin filament has been shown to modulate properties of the filament, thus making it a pivotal regulator of the actin life cycle. Actin has evolved to selectively hydrolyze ATP in the filamentous form, F-actin, with an experimentally observed rate increase over the monomeric form, G-actin, of 4.3 × 10(4). The cause of this dramatic increase in rate is investigated in this paper using extensive QM/MM simulations of both G- and F-actin. To compute the free energy of hydrolysis in both systems, metadynamics is employed along two collective variables chosen to describe the reaction coordinates of hydrolysis. F-actin is modeled as a monomer with restraints applied to coarse-grained variables enforced to keep it in a filament-like conformation. The simulations reveal a barrier height reduction for ATP hydrolysis in F-actin as compared to G-actin of 8 ± 1 kcal/mol, in good agreement with the experimentally measured barrier height reduction of 7 ± 1 kcal/mol. The barrier height reduction is influenced by an enhanced rotational diffusion of water in F-actin as compared to G-actin and shorter water wires between Asp154 and the nucleophilic water in F-actin, leading to more rapid proton transport.

SUBMITTER: McCullagh M

PROVIDER: S-EPMC4183606 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Unraveling the mystery of ATP hydrolysis in actin filaments.

McCullagh Martin M Saunders Marissa G MG Voth Gregory A GA

Journal of the American Chemical Society 20140909 37

Actin performs its myriad cellular functions by the growth and disassembly of its filamentous form. The hydrolysis of ATP in the actin filament has been shown to modulate properties of the filament, thus making it a pivotal regulator of the actin life cycle. Actin has evolved to selectively hydrolyze ATP in the filamentous form, F-actin, with an experimentally observed rate increase over the monomeric form, G-actin, of 4.3 × 10(4). The cause of this dramatic increase in rate is investigated in t ...[more]

PMID: 25181471

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Project description:Actin filaments continually assemble and disassemble within a cell. Assembled filaments "age" as a bound nucleotide ATP within each actin subunit quickly hydrolyzes followed by a slower release of the phosphate Pi, leaving behind a bound ADP. This subtle change in nucleotide state of actin subunits affects filament rigidity as well as its interactions with binding partners. We present here a systematic multiscale ultra-coarse-graining approach that provides a computationally efficient way to simulate a long actin filament undergoing ATP hydrolysis and phosphate-release reactions while systematically taking into account available atomistic details. The slower conformational changes and their dependence on the chemical reactions are simulated with the ultra-coarse-graining model by assigning internal states to the coarse-grained sites. Each state is represented by a unique potential surface of a local heterogeneous elastic network. Internal states undergo stochastic transitions that are coupled to conformations of the underlying molecular system. The model reproduces mechanical properties of the filament and allows us to study whether conformational fluctuations in actin subunits produce cooperative filament aging. We find that the nucleotide states of neighboring subunits modulate the reaction kinetics, implying cooperativity in ATP hydrolysis and Pi release. We further systematically coarse grain the system into a Markov state model that incorporates assembly and disassembly, facilitating a direct comparison with previously published models. We find that cooperativity in ATP hydrolysis and Pi release significantly affects the filament growth dynamics only near the critical G-actin concentration, whereas far from it, both cooperative and random mechanisms show similar growth dynamics. In contrast, filament composition in terms of the bound nucleotide distribution varies significantly at all monomer concentrations studied. These results provide new insights, to our knowledge, into the cooperative nature of ATP hydrolysis and Pi release and the implications it has for actin filament properties, providing novel predictions for future experimental studies.

Dataset Information

Unraveling the mystery of ATP hydrolysis in actin filaments.

Publications

Unraveling the mystery of ATP hydrolysis in actin filaments.

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