TY - JOUR
T1 - Insights into the Cooperative Nature of ATP Hydrolysis in Actin Filaments
AU - Katkar, Harshwardhan H.
AU - Davtyan, Aram
AU - Durumeric, Aleksander E.P.
AU - Hocky, Glen M.
AU - Schramm, Anthony C.
AU - De La Cruz, Enrique M.
AU - Voth, Gregory A.
N1 - Funding Information:
This research was supported in part by the National Science Foundation (NSF) through NSF grant CHE-1465248 and in part by the Department of Defense Army Research Office through Multidisciplinary University Research Initiative grant W911NF1410403. The computations in this work used the Extreme Science and Engineering Discovery Environment, which is supported by NSF grant number ACI-1548562. Additional computational resources were provided by the Research Computing Center at The University of Chicago. G.M.H. was supported by a Ruth L. Kirschstein National Research Service Award (National Institute of General Medical Sciences, F32 GM11345-01). A.E.P.D. acknowledges support by the Department of Defense through the National Defense Science & Engineering Graduate Fellowship Program. E.M.D.L.C. and A.C.S. were supported by the National Institutes of Health through grant R01-GM097348.
Funding Information:
This research was supported in part by the National Science Foundation (NSF) through NSF grant CHE-1465248 and in part by the Department of Defense Army Research Office through Multidisciplinary University Research Initiative grant W911NF1410403 . The computations in this work used the Extreme Science and Engineering Discovery Environment, which is supported by NSF grant number ACI-1548562 . Additional computational resources were provided by the Research Computing Center at The University of Chicago. G.M.H. was supported by a Ruth L. Kirschstein National Research Service Award ( National Institute of General Medical Sciences , F32 GM11345-01 ). A.E.P.D. acknowledges support by the Department of Defense through the National Defense Science & Engineering Graduate Fellowship Program. E.M.D.L.C. and A.C.S. were supported by the National Institutes of Health through grant R01-GM097348 .
Publisher Copyright:
© 2018 Biophysical Society
PY - 2018/10/16
Y1 - 2018/10/16
N2 - 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.
AB - 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.
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U2 - 10.1016/j.bpj.2018.08.034
DO - 10.1016/j.bpj.2018.08.034
M3 - Article
C2 - 30249402
AN - SCOPUS:85053689817
SN - 0006-3495
VL - 115
SP - 1589
EP - 1602
JO - Biophysical Journal
JF - Biophysical Journal
IS - 8
ER -