Collective motions in proteins: A covariance analysis of atomic fluctuations in molecular dynamics and normal mode simulations

Ichiye, Toshiko; Karplus, Martin

doi:10.1002/prot.340110305

Cited by 883 publications

(792 citation statements)

References 19 publications

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“…In the second method, regions of the protein that show correlated and anticorrelated movements were examined using the covariance analysis method of Ichiye and Karplus. 45 The conformational change associated with ATP binding in biotin carboxylase is best described as a hinge motion 46 where the B-domain moves relative to the other domains of the protein. 47 Comparison of the ATP-bound and the apoenzyme suggests that the hinge in biotin carboxylase is located in random loops of the polypeptide chain that link the B-domain with the A-and C-domains.…”

Section: Resultsmentioning

confidence: 99%

Molecular Dynamics Simulations of Biotin Carboxylase

2008

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Biotin carboxylase catalyzes the ATP-dependent carboxylation of biotin and is one component of the multienzyme complex acetyl-CoA carboxylase that catalyzes the first committed step in fatty acid synthesis in all organisms. Biotin carboxylase from Escherichia coli, whose crystal structures with and without ATP bound have been determined, has served as a model system for this component of the acetyl-CoA carboxylase complex. The two crystal structures revealed a large conformational change of one domain relative to the other domains when ATP is bound. Unfortunately, the crystal structure with ATP bound was obtained with an inactive site-directed mutant of the enzyme. As a consequence the structure with ATP bound lacked key structural information such as for the Mg 2+ ions and contained altered conformations of key active-site residues. Therefore, nanosecond molecular dynamics studies of the wild-type biotin carboxylase were undertaken to supplant and amend the results of the crystal structures. Specifically, the protein-metal interactions of the two catalytically critical Mg 2+ ions bound in the active site are presented along with a reevaluation of the conformations of active-site residues bound to ATP. In addition, the regions of the polypeptide chain that serve as hinges for the large conformational change were identified. The results of the hinge analysis complemented a covariance analysis that identified the individual structural elements of biotin carboxylase that change their conformation in response to ATP binding.Acetyl-CoA carboxylase (ACC) catalyzes the first committed step in the biosynthesis of long-chain fatty acids. ACC is a biotin-dependent enzyme found in all bacteria, plants, and animals. Since fatty acids are used for membrane biogenesis and energy storage, ACC is a target for antibiotics, 1,2 herbicides, 3 and antiobesity agents. [4][5][6] ACC produces malonyl-CoA from acetyl-CoA, ATP, and bicarbonate, which serves as the source of CO 2 for all biotindependent carboxylases. 7 The reaction mechanism proceeds via two half-reactions (Scheme 1): (1) the first half-reaction is catalyzed by biotin carboxylase (BC), and (2) the second halfreaction is catalyzed by carboxyltransferase (CT). In vivo, the vitamin biotin is covalently attached to a protein called the biotin carboxyl carrier protein (designated as enzyme-biotin in Scheme 1). In mammals, these proteins comprise different domains in a single polypeptide chain. 8 In contrast, in Gramnegative and Gram-positive bacteria biotin carboxylase, carboxyltransferase, and the biotin carboxyl carrier protein are separate proteins. 9 ACC from the Gram-negative bacterium Escherichia coli has been used as a model system for mechanistic investigations because the purified BC and CT components retain their activities, and utilize free biotin as a substrate, thereby simplifying kinetic analysis. 10 Consequently, biotin carboxylase from E. coli has been extensively studied by X-ray crystallography 11,12 and site-directed mutagenesis. [13][14][15][16] Structural...

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Section: Resultsmentioning

confidence: 99%

Molecular Dynamics Simulations of Biotin Carboxylase

2008

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“…Previous studies have shown that for simulations of native states, regions of secondary structure were found to move in a correlated matter, whereas the significant anti-correlated motions for residues close in space were predicted to be destabilizing to protein structure (24,52). As shown in Figure 6, the neighboring strands in the same -sheet move in a correlated manner, with the exception of no correlated motion between the D and A strands that are thus proven to be weakly coupled.…”

Section: Val30 F Met and Leu55 F Pro Mutations Disrupt The Side Chainmentioning

confidence: 86%

The Sequence-Dependent Unfolding Pathway Plays a Critical Role in the Amyloidogenicity of Transthyretin

et al. 2006

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Human transthyretin (TTR) is an amyloidogenic protein whose aggregation is associated with several types of amyloid diseases. The following mechanism of TTR amyloid formation has been proposed. TTR tetramer at first dissociates into native monomers, which is the rate-limiting step in fibril formation. The monomeric species then partially unfold to form amyloidogenic intermediates that subsequently undergo a downhill self-assembly process. The amyloid deposit can be facilitated by disease-associated point mutations. However, only subtle structural differences were observed between the crystal structures of the wild type and the disease-associated variants. To investigate how single-point mutations influence the effective energy landscapes of TTR monomers, molecular dynamics (MD) simulations were performed on wild-type TTR and two pathogenic variants. Principal coordinate analysis on MD-generated ensembles has revealed multiple unfolding pathways for each protein. Amyloidogenic intermediates with the dislocated C strand-loop-D strand motif were observed only on the unfolding pathways of V30M and L55P variants and not for wild-type TTR. Our study suggests that the sequence-dependent unfolding pathway plays a crucial role in the amyloidogenicity of TTR. Analyses of side chain concerted motions indicate that pathogenic mutations on "edge strands" disrupt the delicate side chain correlated motions, which in turn may alter the sequence of unfolding events.

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“…Secondly, covariance between atomic displacements is calculated between the different conformers, and analysing these covariance values allows identifying motions involving large numbers of atoms. Generally, a small set of collective motions, the first few principal components (PCs), capture the majority of fluctuations in biological macromolecules, and often these dominant motions have been found to be relevant for biological activities 40,41 . In a third step, the conformational changes corresponding to motions along each PC can be back calculated and visualized as a series of snapshots taken along the trajectories.…”

Section: Saxs Experimentsmentioning

confidence: 99%

Structure of the full-length HCV IRES in solution

et al. 2013

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The 5 0 -untranslated region of the hepatitis C virus genome contains an internal ribosome entry site (IRES) that initiates cap-independent translation of the viral RNA. Until now, the structural characterization of the entire (IRES) remained limited to cryo-electron microscopy reconstructions of the (IRES) bound to different cellular partners. Here we report an atomic model of free full-length hepatitis C virus (IRES) refined by selection against small-angle X-ray scattering data that incorporates the known structures of different fragments. We found that an ensemble of conformers reproduces small-angle X-ray scattering data better than a single structure suggesting in combination with molecular dynamics simulations that the hepatitis C virus (IRES) is an articulated molecule made of rigid parts that move relative to each other. Principal component analysis on an ensemble of physically accessible conformers of hepatitis C virus (IRES) revealed dominant collective motions in the molecule, which may underlie the conformational changes occurring in the (IRES) molecule upon formation of the initiation complex.

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Collective motions in proteins: A covariance analysis of atomic fluctuations in molecular dynamics and normal mode simulations

Cited by 883 publications

References 19 publications

Molecular Dynamics Simulations of Biotin Carboxylase

Molecular Dynamics Simulations of Biotin Carboxylase

The Sequence-Dependent Unfolding Pathway Plays a Critical Role in the Amyloidogenicity of Transthyretin

Structure of the full-length HCV IRES in solution

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