MODE-TASK: large-scale protein motion tools

Ross, Caroline Jane; Nizami, Bilal; Glenister, Michael; Amamuddy, Olivier Sheik; Atılgan, Ali Rana; Atılgan, Canan; Bishop, Özlem Taştan

doi:10.1093/bioinformatics/bty427

Cited by 37 publications

(41 citation statements)

References 18 publications

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“…The collective motions of the protein-membrane-water systems were analysed by extracting the top principal components (PCs) using the GROMACS utility toolkits applied to the main-chain atoms, and MODE-TASK. 85 We performed singular value decomposition PCA on alpha carbons (1355 atoms for C83 and 1363 for Notch100) for both systems, and the trajectories were prepared by removing periodicity and water molecules. The lipid binding occupancy was determined using VMD.…”

Section: Dynamic Trajectory Analysismentioning

confidence: 99%

Side-by-side comparison of Notch- and C83 binding to γ-secretase in a complete membrane model at physiological temperature

et al. 2020

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Section: Dynamic Trajectory Analysismentioning

confidence: 99%

Side-by-side comparison of Notch- and C83 binding to γ-secretase in a complete membrane model at physiological temperature

et al. 2020

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“…In contrast, non-degenerate modes characterize unique directions of motions that often capture global meaningful motions that account for large conformational changes. Previous studies showed that dominant conformational changes of complexes were captured within the slowest non-degenerate modes (Atilgan et al, 2001;Chennubhotla et al, 2005;Shrivastava and Bahar, 2006;Wako and Endo, 2011;Isin et al, 2012;Lee et al, 2017;Ross et al, 2018). Here, we identified eight non-degenerate modes of PTPS.…”

Section: Resultsmentioning

confidence: 77%

“…NMA was predominantly performed using the MODE-TASK tool suite (Ross et al, 2018) which employs the ANM (Atilgan et al, 2001) to construct an ENM of the protein structure. Although the ANM has been described previously (Atilgan et al, 2001), we provide a summary here.…”

Section: Calculation Of the Normal Modesmentioning

confidence: 99%

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Probing the Structural Dynamics of the Plasmodium falciparum Tunneling-Fold Enzyme 6-Pyruvoyl Tetrahydropterin Synthase to Reveal Allosteric Drug Targeting Sites

Khairallah

Ross

Bishop

2020

Front. Mol. Biosci.

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The de novo folate synthesis pathway is a well-established drug target in the treatment of many infectious diseases. Antimalarial antifolate drugs have proven to be effective against malaria, however, rapid drug resistance has emerged on the two primary targeted enzymes: dihydrofolate reductase and dihydroptoreate synthase. The need to identify alternative antifolate drugs and novel metabolic targets is of imminent importance. The 6-pyruvol tetrahydropterin synthase (PTPS) enzyme belongs to the tunneling fold protein superfamily which is characterized by a distinct central tunnel/cavity. The enzyme catalyzes the second reaction step of the parasite's de novo folate synthesis pathway and is responsible for the conversion of 7,8-dihydroneopterin to 6-pyruvoyl-tetrahydropterin. In this study, we examine the structural dynamics of Plasmodium falciparum PTPS using the anisotropic network model, to elucidate the collective motions that drive the function of the enzyme and identify potential sites for allosteric modulation of its binding properties. Based on our modal analysis, we identified key sites in the N-terminal domains and central helices which control the accessibility to the active site. Notably, the N-terminal domains were shown to regulate the open-toclosed transition of the tunnel, via a distinctive wringing motion that deformed the core of the protein. We, further, combined the dynamic analysis with motif discovery which revealed highly conserved motifs that are unique to the Plasmodium species and are located in the N-terminal domains and central helices. This provides essential structural information for the efficient design of drugs such as allosteric modulators that would have high specificity and low toxicity as they do not target the PTPS active site that is highly conserved in humans.

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“…Since all springs are in a relaxed state in the network, no energy minimization is required, in comparison to normal mode analysis in which an expensive initial energy minimization is required prior to calculating the Hessian matrix. For large biomolecules and multi-protein complexes, ENM models with a resolution lower than standard have been used ( Durand et al, 1994 ; Doruker et al, 2002 ; Chennubhotla et al, 2005 ; Ahmed and Gohlke, 2006 ; Kurkcuoglu et al, 2009 ; Ross C. et al, 2018 ). The gross representation of large assemblies has proven to predict dynamics of the rigid and flexible parts of the proteins ( Ross C.J.…”

Section: Introductionmentioning

confidence: 99%

A Coarse-Grained Methodology Identifies Intrinsic Mechanisms That Dissociate Interacting Protein Pairs

Abdizadeh

Jalalypour

Atılgan

et al. 2020

Front. Mol. Biosci.

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We address the problem of triggering dissociation events between proteins that have formed a complex. We have collected a set of 25 non-redundant, functionally diverse protein complexes having high-resolution three-dimensional structures in both the unbound and bound forms. We unify elastic network models with perturbation response scanning (PRS) methodology as an efficient approach for predicting residues that have the propensity to trigger dissociation of an interacting protein pair, using the three-dimensional structures of the bound and unbound proteins as input. PRS reveals that while for a group of protein pairs, residues involved in the conformational shifts are confined to regions with large motions, there are others where they originate from parts of the protein unaffected structurally by binding. Strikingly, only a few of the complexes have interface residues responsible for dissociation. We find two main modes of response: In one mode, remote control of dissociation in which disruption of the electrostatic potential distribution along protein surfaces play the major role; in the alternative mode, mechanical control of dissociation by remote residues prevail. In the former, dissociation is triggered by changes in the local environment of the protein, e.g., pH or ionic strength, while in the latter, specific perturbations arriving at the controlling residues, e.g., via binding to a third interacting partner is required for decomplexation. We resolve the observations by relying on an electromechanical coupling model which reduces to the usual elastic network result in the limit of the lack of coupling. We validate the approach by illustrating the biological significance of top residues selected by PRS on select cases where we show that the residues whose perturbation leads to the observed conformational changes correspond to either functionally important or highly conserved residues in the complex.

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MODE-TASK: large-scale protein motion tools

Cited by 37 publications

References 18 publications

Side-by-side comparison of Notch- and C83 binding to γ-secretase in a complete membrane model at physiological temperature

Side-by-side comparison of Notch- and C83 binding to γ-secretase in a complete membrane model at physiological temperature

Probing the Structural Dynamics of the Plasmodium falciparum Tunneling-Fold Enzyme 6-Pyruvoyl Tetrahydropterin Synthase to Reveal Allosteric Drug Targeting Sites

A Coarse-Grained Methodology Identifies Intrinsic Mechanisms That Dissociate Interacting Protein Pairs

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