Dataset Information

Coupling between normal modes drives protein conformational dynamics: illustrations using allosteric transitions in myosin II.

ABSTRACT: Structure-based elastic network models (ENMs) have been remarkably successful in describing conformational transitions in a variety of biological systems. Low-frequency normal modes are usually calculated from the ENM that characterizes elastic interactions between residues in contact in a given protein structure with a uniform force constant. To explore the dynamical effects of nonuniform elastic interactions, we calculate the robustness and coupling of the low-frequency modes in the presence of nonuniform variations in the ENM force constant. The variations in the elastic interactions, approximated here by Gaussian noise, approximately account for perturbation effects of heterogeneous residue-residue interactions or evolutionary sequence changes within a protein family. First-order perturbation theory provides an efficient and qualitatively correct estimate of the mode robustness and mode coupling for finite perturbations to the ENM force constant. The mode coupling analysis and the mode robustness analysis identify groups of strongly coupled modes that encode for protein functional motions. We illustrate the new concepts using myosin II motor protein as an example. The biological implications of mode coupling in tuning the allosteric couplings among the actin-binding site, the nucleotide-binding site, and the force-generating converter and lever arm in myosin isoforms are discussed. We evaluate the robustness of the correlation functions that quantify the allosteric couplings among these three key structural motifs.

SUBMITTER: Zheng W

PROVIDER: S-EPMC2717279 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

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Coupling between normal modes drives protein conformational dynamics: illustrations using allosteric transitions in myosin II.

Zheng Wenjun W Thirumalai D D

Biophysical journal 20090301 6

Structure-based elastic network models (ENMs) have been remarkably successful in describing conformational transitions in a variety of biological systems. Low-frequency normal modes are usually calculated from the ENM that characterizes elastic interactions between residues in contact in a given protein structure with a uniform force constant. To explore the dynamical effects of nonuniform elastic interactions, we calculate the robustness and coupling of the low-frequency modes in the presence o ...[more]

PMID: 19289039

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Project description:Conventional myosin is representative of biomolecular motors in which the hydrolysis of adenosine triphosphate (ATP) is coupled to large-scale structural transitions both in and remote from the active site. The mechanism that underlies such "mechanochemical coupling," especially the causal relationship between hydrolysis and allosteric structural changes, has remained elusive despite extensive experimental and computational analyses. In this study, using combined quantum mechanical and molecular mechanical simulations and different conformations of the myosin motor domain, we provide evidence to support that regulation of ATP hydrolysis activity is not limited to residues in the immediate environment of the phosphate. Specifically, we illustrate that efficient hydrolysis of ATP depends not only on the proper orientation of the lytic water but also on the structural stability of several nearby residues, especially the Arg238-Glu459 salt bridge (the numbering of residues follows myosin II in Dictyostelium discoideum) and the water molecule that spans this salt bridge and the lytic water. More importantly, by comparing the hydrolysis activities in two motor conformations with very similar active-site (i.e., Switches I and II) configurations, which distinguished this work from our previous study, the results clearly indicate that the ability of these residues to perform crucial electrostatic stabilization relies on the configuration of residues in the nearby N-terminus of the relay helix and the "wedge loop." Without the structural support from those motifs, residues in a closed active site in the post-rigor motor domain undergo subtle structural variations that lead to consistently higher calculated ATP hydrolysis barriers than in the pre-powerstroke state. In other words, starting from the post-rigor state, turning on the ATPase activity requires not only displacement of Switch II to close the active site but also structural transitions in the N-terminus of the relay helix and the "wedge loop," which have been proposed previously to be ultimately coupled to the rotation of the converter subdomain 40 A away.

Dataset Information

Coupling between normal modes drives protein conformational dynamics: illustrations using allosteric transitions in myosin II.

Publications

Coupling between normal modes drives protein conformational dynamics: illustrations using allosteric transitions in myosin II.

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