Global motions exhibited by proteins in micro- to milliseconds simulations concur with anisotropic network model predictions

Gür, Mert; Zomot, Elia; Bahar, İvet

doi:10.1063/1.4816375

Cited by 77 publications

(76 citation statements)

References 58 publications

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“…In a recent study comparing soft modes derived from network models (such as ENM and ANM) to principal components derived from a millisecond-long Anton molecular dynamics simulation [39], the three lowest-frequency ANM modes captured the backbone conformations and motions observed in the first five principal components of the MD simulation [40••. In other words, the network method successfully identified the first three sub-states of the MD-generated energy landscape, but not the remaining five.…”

Section: Different Methods Sample Different Allosteric Timescales Momentioning

confidence: 99%

Computational approaches to mapping allosteric pathways

Feher

Durrant

Wart

et al. 2014

Current Opinion in Structural Biology

128

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Allosteric signaling occurs when chemical and/or physical changes at an allosteric site alter the activity of a primary orthosteric site often many Angstroms distant. A number of recently developed computational techniques, including dynamical network analysis, novel topological and molecular dynamics methods, and hybrids of these methods are useful for elucidating allosteric signaling pathways at the atomistic level. No single method prevails as best to identify allosteric signal propagation path(s), rather each has particular strengths in characterizing signals that occur over a specific timescale range and magnitude of conformational fluctuation. With continued improvement of accuracy and predictive power, these computational techniques aim to become useful drug discovery tools that will allow researchers to identify allostery critical residues for subsequent pharmacological targeting.

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Section: Different Methods Sample Different Allosteric Timescales Momentioning

confidence: 99%

Computational approaches to mapping allosteric pathways

Feher

Durrant

Wart

et al. 2014

Current Opinion in Structural Biology

128

View full text Add to dashboard Cite

show abstract

“…the amplitude of the excursions of the nSH2 away from the helical and the kinase domains should be larger. One way to look at these motions is to use of normal mode analysis (Eyal et al 2011; Gur et al 2013). Normal mode analysis of the helical domain double mutants E542K/E545K and E542R/ E545R shows that, in both cases, the nSH2 domain of p85 experiences a much larger amplitude of movement (expressed as the average fluctuations) than in the WT protein (Fig.…”

Section: Introductionmentioning

confidence: 99%

Activation of PI3Kα by physiological effectors and by oncogenic mutations: structural and dynamic effects

et al. 2014

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PI3Kα, a heterodimeric lipid kinase, catalyzes the conversion of phosphoinositide-4,5-bisphosphate (PIP2) to phosphoinositide-3,4,5-trisphosphate (PIP3), a lipid that recruits to the plasma membrane proteins that regulate signaling cascades that control key cellular processes such as cell proliferation, carbohydrate metabolism, cell motility, and apoptosis. PI3Kα is composed of two subunits, p110α and p85, that are activated by binding to phosphorylated receptor tyrosine kinases (RTKs) or their substrates. The gene coding for p110α, PIK3CA, has been found to be mutated in a large number of tumors; these mutations result in increased PI3Kα kinase activity. The structure of the complex of p110α with a fragment of p85 containing the nSH2 and the iSH2 domains has provided valuable information about the mechanisms underlying the physiological activation of PI3Kα and its pathological activation by oncogenic mutations. This review discusses information derived from x-ray diffraction and theoretical calculations regarding the structural and dynamic effects of mutations in four highly mutated regions of PI3K p110α, as well as the proposed mechanisms by which these mutations increase kinase activity. During the physiological activation of PI3Kα, the phosphorylated tyrosine of RTKs binds to the nSH2 domain of p85, dislodging an inhibitory interaction between the p85 nSH2 and a loop of the helical domain of p110α. Several of the oncogenic mutations in p110α activate the enzyme by weakening this autoinhibitory interaction. These effects involve structural changes as well as changes in the dynamics of the enzyme. One of the most common p110α mutations, H1047R, activates PI3Kα by a different mechanism: it increases the interaction of the enzyme with the membrane, maximizing the access of the PI3Kα to its substrate PIP2, a membrane lipid.

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“…Subsequently, MD snapshots were projected onto this principal frame. The occupancy of different grids on the surface, also called distributions of conformations, f (R), was computed to estimate the free energy as A (R) = −kT ln { f (R)} + ct. 39 The free energy surface projected on the PCs 1-2 is shown in Fig. 1(a).…”

Section: A Energy Landscape Based On 21 µS Cmd Simulations Shows Mulmentioning

confidence: 99%

Energy landscape of LeuT from molecular simulations

Gür

Zomot

Cheng

et al. 2015

The Journal of Chemical Physics

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The bacterial sodium-coupled leucine transporter (LeuT) has been broadly used as a structural model for understanding the structure-dynamics-function of mammalian neurotransmitter transporters as well as other solute carriers that share the same fold (LeuT fold), as the first member of the family crystallographically resolved in multiple states: outward-facing open, outward-facing occluded, and inward-facing open. Yet, a complete picture of the energy landscape of (sub)states visited along the LeuT transport cycle has been elusive. In an attempt to visualize the conformational spectrum of LeuT, we performed extensive simulations of LeuT dimer dynamics in the presence of substrate (Ala or Leu) and co-transported Na + ions, in explicit membrane and water. We used both conventional molecular dynamics (MD) simulations (with Anton supercomputing machine) and a recently introduced method, collective MD, that takes advantage of collective modes of motions predicted by the anisotropic network model. Free energy landscapes constructed based on ∼40 µs trajectories reveal multiple substates occluded to the extracellular (EC) and/or intracellular (IC) media, varying in the levels of exposure of LeuT to EC or IC vestibules. The IC-facing transmembrane (TM) helical segment TM1a shows an opening, albeit to a smaller extent and in a slightly different direction than that observed in the inward-facing open crystal structure. The study provides insights into the spectrum of conformational substates and paths accessible to LeuT and highlights the differences between Ala-and Leu-bound substates. C 2015 AIP Publishing LLC. [http://dx

show abstract

Global motions exhibited by proteins in micro- to milliseconds simulations concur with anisotropic network model predictions

Cited by 77 publications

References 58 publications

Computational approaches to mapping allosteric pathways

Computational approaches to mapping allosteric pathways

Activation of PI3Kα by physiological effectors and by oncogenic mutations: structural and dynamic effects

Energy landscape of LeuT from molecular simulations

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