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Allostery of actin filaments: molecular dynamics simulations and coarse-grained analysis.

ABSTRACT: The structural and mechanical properties of monomeric actin (G-actin), the trimer nucleus, and actin filaments (F-actins) are determined as a function of the conformation of the DNase I-binding loop (DB loop) by using all-atom molecular dynamics simulations and coarse-grained (CG) analysis. Recent x-ray structures of ADP-bound G-actin (G-ADP) by Otterbein et al. [Otterbein, L. R., Graceffa, P. & Dominguez, R. (2001) Science 293, 708-711] and ATP-bound G-actin (G-ATP) by Graceffa and Dominguez [Graceffa, P. & Dominguez, R. (2003) J. Biol. Chem. 278, 34172-34180] indicate that the DB loop of actin does not have a well defined secondary structure in the ATP state but folds into an alpha-helix in the ADP state. MD simulations and CG analysis indicate that such a helical DB loop significantly weakens the intermonomer interactions of actin assemblies and thus leads to a wider, shorter, and more disordered filament. The computed persistence lengths of F-actin composed of G-ATP (16 microm) and of G-ADP (8.5 microm) agree well with the experimental values for the two states. Therefore, the loop-to-helix transition of the DB loop may be one of the factors that lead to the changes in structural and mechanical properties of F-actin after ATP hydrolysis. This result may provide a direct connection between the conformational changes of an actin monomer and the structural and mechanical properties of the cytoskeleton. The information provided by MD simulations also helps to understand the possible origin of the special features of actin dynamics.

SUBMITTER: Chu JW

PROVIDER: S-EPMC1201585 | biostudies-literature | 2005 Sep

REPOSITORIES: biostudies-literature

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Allostery of actin filaments: molecular dynamics simulations and coarse-grained analysis.

Chu Jhih-Wei JW Voth Gregory A GA

Proceedings of the National Academy of Sciences of the United States of America 20050831 37

The structural and mechanical properties of monomeric actin (G-actin), the trimer nucleus, and actin filaments (F-actins) are determined as a function of the conformation of the DNase I-binding loop (DB loop) by using all-atom molecular dynamics simulations and coarse-grained (CG) analysis. Recent x-ray structures of ADP-bound G-actin (G-ADP) by Otterbein et al. [Otterbein, L. R., Graceffa, P. & Dominguez, R. (2001) Science 293, 708-711] and ATP-bound G-actin (G-ATP) by Graceffa and Dominguez [G ...[more]

PMID: 16135566

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Project description:Microtubules are long polymers of alphabeta-tubulin heterodimers. They undergo a process known as dynamic instability, in which the ends of a microtubule switch stochastically between phases of slow growth and rapid shrinkage. The molecular mechanisms inducing the depolymerization of microtubules were attributed to the hydrolysis of the guanosine triphosphate (GTP) nucleotide bound to the beta-tubulin. The hydrolysis of GTP is thought to cause microtubule instability by promoting outward curving of the protofilaments constituting the microtubule lattice. The bending of protofilaments is associated with the structural transformation of a tubulin dimer from straight to curved conformations. However, the nature of intrinsic bending of the dimer remains elusive. This study uses molecular dynamics (MD) simulations and coarse-grained analysis to reveal the intrinsic bending, as well as the local structural rearrangements, of the unassembled tubulin dimer as the dimer relaxes from its lattice-constrained, straight conformation of a zinc-induced tubulin sheet. The effect of the nucleotide state on dimer-bending is investigated by the introduction of gamma-phosphate into the beta-tubulin to form GTP-bound tubulin. In agreement with recent experimental studies that proposed nucleotide-independent curved conformations, both guanosine diphosphate (GDP)-bound and GTP-bound tubulin dimers were found to have curved conformations, but with a tendency toward smaller bending in the GTP-tubulin than in the GDP-tubulin. The perturbation induced through the introduction of gamma-phosphate is posited to play a role in straightening the intradimer bending. The local structural rearrangements of GDP-tubulin because of the bending mode of motion of the dimer reveal that one of the three functional domains, the intermediate domain, exhibits significantly lower bending deformation compared with the others, signifying a dynamic connection to the functionally defined domains.

Dataset Information

Allostery of actin filaments: molecular dynamics simulations and coarse-grained analysis.

Publications

Allostery of actin filaments: molecular dynamics simulations and coarse-grained analysis.

Similar Datasets

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