Multiscale Ensemble Modeling of Intrinsically Disordered Proteins: p53 N-Terminal Domain

Terakawa, Tsuyoshi; Takada, Shoji

doi:10.1016/j.bpj.2011.08.003

Cited by 101 publications

(99 citation statements)

References 51 publications

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“…These results motivated us to make the domain III-IV linker region flexible (38). The flexible linker is further justified by the following arguments: (i) When we constructed the E. coli DnaA domain III-IV homology model, the secondary structure prediction of the I-TASSER modeling server suggests that the linker tends to form loops rather than an α-helix (37).…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Near-atomic structural model for bacterial DNA replication initiation complex and its functional insights

Shimizu

Noguchi

Sakiyama

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Upon DNA replication initiation in Escherichia coli, the initiator protein DnaA forms higher-order complexes with the chromosomal origin oriC and a DNA-bending protein IHF. Although tertiary structures of DnaA and IHF have previously been elucidated, dynamic structures of oriC-DnaA-IHF complexes remain unknown. Here, combining computer simulations with biochemical assays, we obtained models at almost-atomic resolution for the central part of the oriC-DnaA-IHF complex. This complex can be divided into three subcomplexes; the left and right subcomplexes include pentameric DnaA bound in a head-to-tail manner and the middle subcomplex contains only a single DnaA. In the left and right subcomplexes, DnaA ATPases associated with various cellular activities (AAA+) domain III formed helices with specific structural differences in interdomain orientations, provoking a bend in the bound DNA. In the left subcomplex a continuous DnaA chain exists, including insertion of IHF into the DNA looping, consistent with the DNA unwinding function of the complex. The intervening spaces in those subcomplexes are crucial for DNA unwinding and loading of DnaB helicases. Taken together, this model provides a reasonable near-atomic level structural solution of the initiation complex, including the dynamic conformations and spatial arrangements of DnaA subcomplexes.DnaA | molecular simulation | coarse-grained model | oriC C hromosomal DNA replication is initiated by unwinding the dsDNA of the replication origin, which requires formation of higher-order protein-DNA complexes, typically referred to as the initiation complexes (1). DnaA is a major replication initiation protein conserved in the initiation complex of most eubacterial species. In a model organism, Escherichia coli, DnaA forms homooligomers on the replication origin oriC, which promotes dsDNA unwinding. The resulting ssDNA is captured by DnaB helicase, followed by formation of the replisomes (2-5). Molecular mechanisms of how DnaA facilitates dsDNA unwinding are still unclear, although some models have been proposed (1, 6-10). A high-resolution structure model of the initiation complex, discovered using computational modeling based on experimental data, would provide significant insight into the molecular mechanism.The E. coli minimal oriC region contains the AT-rich DNA unwinding element (DUE), at least 11 DnaA-binding motifs (termed DnaA boxes) and a single binding site for the integration host factor (IHF) (Fig. 1A) (1-5, 11-15). The DnaA boxes contain 9-mer nucleotides (consensus sequence TTATNCACA, where N can be any base) (16). The 11 DnaA boxes (R1-2, R4, R5M, I1-3, C1-3, and τ2) have differing affinities to DnaA and motif orientations (indicated by triangles in Fig. 1A): The two terminal boxes R1 and R4 have especially high affinities (dissociation constants 1-6 nM for R1 and ∼1 nM for R4), whereas others have modest (R2) to low affinities (I1-3, C1-3, and R5M and τ2; dissociation constants for R5M are >200 nM) (12-19). The 11 DnaA boxes have been divided into two groups...

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Section: Resultsmentioning

confidence: 99%

“…First, we used a flexible linker model (38) for the linker between domains III and IV. The flexibility could be somewhat overestimated.…”

Section: Discussionmentioning

confidence: 99%

Near-atomic structural model for bacterial DNA replication initiation complex and its functional insights

Shimizu

Noguchi

Sakiyama

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Such effect of phosphorylation on the intrinsic propensity toward certain local backbone conformations can be especially important for intrinsically disordered proteins, for which the long-range global interactions are less significant compared to those of well-structured proteins. In addition, the intrinsic propensity toward certain local backbone conformations of a certain amino acid is also an important input for some computational models of protein folding/aggregation and structure predictions [11][12][13][14][15][16][17]. For example, recent computational works showed that introducing amino acid-specific parameters to the intrinsic conformational propensity in the all-atom force field can drastically improve protein folding and structure predictions [18,19].…”

Section: Introductionmentioning

confidence: 99%

Effects of phosphorylation on the intrinsic propensity of backbone conformations of serine/threonine

Gao

Zhang

et al. 2016

J Biol Phys

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Each amino acid has its intrinsic propensity for certain local backbone conformations, which can be further modulated by the physicochemical environment and post-translational modifications. In this work, we study the effects of phosphorylation on the intrinsic propensity for different local backbone conformations of serine/threonine by molecular dynamics simulations. We showed that phosphorylation has very different effects on the intrinsic propensity for certain local backbone conformations for the serine and threonine. The phosphorylation of serine increases the propensity of forming polyproline II, whereas that of threonine has the opposite effect. Detailed analysis showed that such different responses to phosphorylation mainly arise from their different perturbations to the backbone hydration and the geometrical constraints by forming sidechain-backbone hydrogen bonds due to phosphorylation. Such an effect of phosphorylation on backbone conformations can be crucial for understanding the molecular mechanism of phosphorylation-regulated protein structures/dynamics and functions.

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“…Last in this chapter, we note that the coarse-grained model is also useful to rationally explain coupled folding and binding, as done by Okazaki and Takada [45], and Terakawa and Takada [56]. Recently, Matsushita and Kikuchi [37] have proposed a novel picture for intrinsic disorder, where structural frustrations are designed for inducing the intrinsic disorder.…”

Section: Coupled Folding and Bindingmentioning

confidence: 91%

Free-Energy Landscape of Intrinsically Disordered Proteins Investigated by All-Atom Multicanonical Molecular Dynamics

Higo

Umezawa

2013

Advances in Experimental Medicine and Biology

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We introduce computational studies on intrinsically disordered proteins (IDPs). Especially, we present our multicanonical molecular dynamics (McMD) simulations of two IDP-partner systems: NRSF-mSin3 and pKID-KIX. McMD is one of enhanced conformational sampling methods useful for conformational sampling of biomolecular systems. IDP adopts a specific tertiary structure upon binding to its partner molecule, although it is unstructured in the unbound state (i.e. the free state). This IDP-specific property is called "coupled folding and binding". The McMD simulation treats the biomolecules with an all-atom model immersed in an explicit solvent. In the initial configuration of simulation, IDP and its partner molecules are set to be distant from each other, and the IDP conformation is disordered. The computationally obtained free-energy landscape for coupled folding and binding has shown that native- and non-native-complex clusters distribute complicatedly in the conformational space. The all-atom simulation suggests that both of induced-folding and population-selection are coupled complicatedly in the coupled folding and binding. Further analyses have exemplified that the conformational fluctuations (dynamical flexibility) in the bound and unbound states are essentially important to characterize IDP functioning.

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Multiscale Ensemble Modeling of Intrinsically Disordered Proteins: p53 N-Terminal Domain

Cited by 101 publications

References 51 publications

Near-atomic structural model for bacterial DNA replication initiation complex and its functional insights

Near-atomic structural model for bacterial DNA replication initiation complex and its functional insights

Effects of phosphorylation on the intrinsic propensity of backbone conformations of serine/threonine

Free-Energy Landscape of Intrinsically Disordered Proteins Investigated by All-Atom Multicanonical Molecular Dynamics

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