Insights into the Cooperative Nature of ATP Hydrolysis in Actin Filaments

Harshwardhan H. Katkar, Aram Davtyan, Aleksander E.P. Durumeric, Glen Hocky, Anthony C. Schramm, Enrique M. De La Cruz, Gregory A. Voth

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1589-1602
Number of pages14
JournalBiophysical Journal
Volume115
Issue number8
DOIs
StatePublished - Oct 16 2018

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Actin Cytoskeleton
Hydrolysis
Adenosine Triphosphate
Actins
Nucleotides
Phosphates
Molecular Conformation
Growth
Adenosine Diphosphate

ASJC Scopus subject areas

  • Biophysics

Cite this

Katkar, H. H., Davtyan, A., Durumeric, A. E. P., Hocky, G., Schramm, A. C., De La Cruz, E. M., & Voth, G. A. (2018). Insights into the Cooperative Nature of ATP Hydrolysis in Actin Filaments. Biophysical Journal, 115(8), 1589-1602. https://doi.org/10.1016/j.bpj.2018.08.034

Insights into the Cooperative Nature of ATP Hydrolysis in Actin Filaments. / Katkar, Harshwardhan H.; Davtyan, Aram; Durumeric, Aleksander E.P.; Hocky, Glen; Schramm, Anthony C.; De La Cruz, Enrique M.; Voth, Gregory A.

In: Biophysical Journal, Vol. 115, No. 8, 16.10.2018, p. 1589-1602.

Research output: Contribution to journalArticle

Katkar, HH, Davtyan, A, Durumeric, AEP, Hocky, G, Schramm, AC, De La Cruz, EM & Voth, GA 2018, 'Insights into the Cooperative Nature of ATP Hydrolysis in Actin Filaments', Biophysical Journal, vol. 115, no. 8, pp. 1589-1602. https://doi.org/10.1016/j.bpj.2018.08.034
Katkar HH, Davtyan A, Durumeric AEP, Hocky G, Schramm AC, De La Cruz EM et al. Insights into the Cooperative Nature of ATP Hydrolysis in Actin Filaments. Biophysical Journal. 2018 Oct 16;115(8):1589-1602. https://doi.org/10.1016/j.bpj.2018.08.034
Katkar, Harshwardhan H. ; Davtyan, Aram ; Durumeric, Aleksander E.P. ; Hocky, Glen ; Schramm, Anthony C. ; De La Cruz, Enrique M. ; Voth, Gregory A. / Insights into the Cooperative Nature of ATP Hydrolysis in Actin Filaments. In: Biophysical Journal. 2018 ; Vol. 115, No. 8. pp. 1589-1602.
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