Exploring the essential collective dynamics of interacting proteins: Application to prion protein dimers

Issack, Bilkiss B.; Berjanskii, Mark V.; Wishart, David S.; Stepanova, Maria

doi:10.1002/prot.24082

Cited by 17 publications

(38 citation statements)

References 112 publications

(161 reference statements)

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“…While these earlier studies reported less conformational sampling and reduced flexibility in PME simulations, several recent simulation studies have used PME and investigated flexible regions and conformational changes in diverse proteins [76], [77], [78], [79]. Hence, the highly stable helix H2 in apo- and holo-forms in the set of PME simulations in the present study indicates that the length of the simulations is not sufficient to observe the H2 destabilization.…”

Section: Discussionmentioning

confidence: 56%

Behavior of Solvent-Exposed Hydrophobic Groove in the Anti-Apoptotic Bcl-XL Protein: Clues for Its Ability to Bind Diverse BH3 Ligands from MD Simulations

Modi

Sankararamakrishnan

2013

PLoS ONE

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Bcl-XL is a member of Bcl-2 family of proteins involved in the regulation of intrinsic pathway of apoptosis. Its overexpression in many human cancers makes it an important target for anti-cancer drugs. Bcl-XL interacts with the BH3 domain of several pro-apoptotic Bcl-2 partners. This helical bundle protein has a pronounced hydrophobic groove which acts as a binding region for the BH3 domains. Eight independent molecular dynamics simulations of the apo/holo forms of Bcl-XL were carried out to investigate the behavior of solvent-exposed hydrophobic groove. The simulations used either a twin-range cut-off or particle mesh Ewald (PME) scheme to treat long-range interactions. Destabilization of the BH3 domain-containing helix H2 was observed in all four twin-range cut-off simulations. Most of the other major helices remained stable. The unwinding of H2 can be related to the ability of Bcl-XL to bind diverse BH3 ligands. The loss of helical character can also be linked to the formation of homo- or hetero-dimers in Bcl-2 proteins. Several experimental studies have suggested that exposure of BH3 domain is a crucial event before they form dimers. Thus unwinding of H2 seems to be functionally very important. The four PME simulations, however, revealed a stable helix H2. It is possible that the H2 unfolding might occur in PME simulations at longer time scales. Hydrophobic residues in the hydrophobic groove are involved in stable interactions among themselves. The solvent accessible surface areas of bulky hydrophobic residues in the groove are significantly buried by the loop LB connecting the helix H2 and subsequent helix. These observations help to understand how the hydrophobic patch in Bcl-XL remains stable in the solvent-exposed state. We suggest that both the destabilization of helix H2 and the conformational heterogeneity of loop LB are important factors for binding of diverse ligands in the hydrophobic groove of Bcl-XL.

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Section: Discussionmentioning

confidence: 56%

Behavior of Solvent-Exposed Hydrophobic Groove in the Anti-Apoptotic Bcl-XL Protein: Clues for Its Ability to Bind Diverse BH3 Ligands from MD Simulations

Modi

Sankararamakrishnan

2013

PLoS ONE

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“…The ECD method employs several descriptors based on the distances d ij . They include the dynamic domains of correlated motions [44], the main-chain flexibility profiles of the protein [45], and the pair correlation maps for main-chain and side-chain atoms [50]. These descriptors are directly comparable with NMR structural data obtained on a longer time scale than required for the ECD analysis [44,45,[48][49][50].…”

Section: Essential Collective Dynamics Analysismentioning

confidence: 93%

“…In globular proteins with developed secondary structure, such as prion proteins, stable a-helices or b-strands are often found in regions of low flexibility. A high value of F Ca , identifies more flexible parts of the protein [45,48,50]. We also use pair correlation descriptor, d ij , obtained directly from the distance between images of atoms i and j in the projected image r i ,…”

Section: Essential Collective Dynamics Analysismentioning

confidence: 99%

“…Our aim is to monitor the evolution of new emerging secondary structures, particularly the formation b-sheet structures, and compare the stability of these structures, in several hypothetical aS constructs starting from their respective unfolded configurations. We also report our analysis of the resulting structures obtained via MD simulations using the novel essential collective dynamics (ECD) methodology [44][45][46][47][48][49][50][51][52][53].…”

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confidence: 99%

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Understanding the dynamics of monomeric, dimeric, and tetrameric α‐synuclein structures in water

Mane

Stepanova

2016

FEBS Open Bio

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Human α‐synuclein (αS) is an intrinsically disordered protein associated with Parkinson's disease. Molecular mechanisms of corruptive misfolding and aggregation of αS resulting in the disease, as well as the structure and other properties of the corresponding oligomers are not entirely understood yet, preventing the development of efficient therapies. In this study, we investigate the folding dynamics of initially unfolded hypothetical αS constructs in water using all‐atom molecular dynamics simulations. We also employ the novel essential collective dynamics method to analyze the results obtained from the simulations. Our comparative analysis of monomeric, dimeric, and tetrameric αS models reveals pronounced differences in their structure and stability, emphasizing the importance of small oligomers, particularly dimers, in the process of misfolding.

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“…In the profile, low levels of the distance denote a stronger correlation. A similar analysis can be employed to assess the binding of proteins to various ligands [13], e.g., other proteins, DNA, etc.…”

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confidence: 99%

Conformational modes in biomolecules: Dynamics and approximate invariance

Potapov

Stepanova

2012

Phys. Rev. E

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Understanding the physical mechanisms behind the folding and conformational dynamics of biomolecules is one of the major unsolved challenges of soft matter theory. In this contribution, a theoretical framework for biomolecular dynamics is introduced, employing selected aspects of statistical mechanics, dimensionality reduction, the perturbation theory, and the theory of matrices. Biomolecular dynamics is represented by time-dependent orthogonal conformational modes, the dynamics of the modes is investigated, and invariant properties that persist are identified. As an example, the dynamics of a human prion protein is considered. The theory provides a rigorous background for assessing the stable dynamical properties of biomolecules, such as their coarse-grained structure, through a multiscale approach using short subnanosecond segments of molecular dynamics trajectories. Furthermore, the paper offers a theoretical platform for models of conformational changes in macromolecules, which may allow complementing molecular dynamics simulations.

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Exploring the essential collective dynamics of interacting proteins: Application to prion protein dimers

Cited by 17 publications

References 112 publications

Behavior of Solvent-Exposed Hydrophobic Groove in the Anti-Apoptotic Bcl-XL Protein: Clues for Its Ability to Bind Diverse BH3 Ligands from MD Simulations

Behavior of Solvent-Exposed Hydrophobic Groove in the Anti-Apoptotic Bcl-XL Protein: Clues for Its Ability to Bind Diverse BH3 Ligands from MD Simulations

Understanding the dynamics of monomeric, dimeric, and tetrameric α‐synuclein structures in water

Conformational modes in biomolecules: Dynamics and approximate invariance

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