Giving Nature a Second Chance: Minimally Invasive Management of a Maxillary Central Incisor with a Severe Traumatic Lesion

Dashti, Deyar; Dashti, M H; Panah, Nahal; Hashemian, Roxana

doi:10.31487/j.jdoa.2020.02.02

Cited by 1 publication

(7 citation statements)

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“…As detailed in Methods, we infer free-energy changes from the population of points on the CC1-CC2 conformational plane via the Boltzmann factor (fig. 1A) ( 6 ). The minimum free energy path on this CC1-CC2 landscape consists of a ‘horse-shoe’ shaped, essentially iso-energetic tube.…”

Section: Resultsmentioning

confidence: 99%

“…The variation in conformations of the spike protein is only partially apparent in a comparison between the reported static apo ( 1, 3 ), holo ( 26–28 ), and long-time MD simulation models of the spike ( 29 ). In contrast, we circumvent the uncertainties in inferring function from stationary snapshots ( 6 ), by compiling density movies along the MFEP to reveal the functional trajectory of the apo spike conformation.…”

Section: Resultsmentioning

confidence: 99%

“…We use geometric machine-learning (ManifoldEM) (23) to extract the manifold of conformational motions from cryo-EM images. This manifold is spanned by a set of orthogonal conformational coordinates (CC) (6). To determine the conformational changes along each coordinate, we compile a 3D movie of the density maps along each of those coordinates.…”

Section: Conformational Coordinates Energy Landscape and Functional Trajectorymentioning

confidence: 99%

“…This landscape is, in principle, multidimensional. Nonetheless, a two-dimensional (2D) representation described by the leading two conformational coordinates is commonly used to project the multidimensional free energy profiles on to a manifold of reduced dimensionality (6)(7)(8). Near equilibrium, biomolecular function corresponds to traversing the minimum-energy pathway connecting the initial and final states (9)(10)(11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

“…It is recognized that the spike protein exhibits structural variability ( 1, 5 ). However, access to an experimentally determined conformational path between the apo- and holo-end states would substantially elucidate the thermally accessible functionally relevant conformational motions of the spike protein ( 6,7 ).…”

Section: Introductionmentioning

confidence: 99%

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Energy Landscape of the SARS-CoV-2 Reveals Extensive Conformational Heterogeneity

Mashayekhi

Vant

Singharoy

et al. 2021

Preprint

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Cryo-electron microscopy (cryo-EM) has produced a number of structural models of the SARS-CoV-2 spike, already prompting biomedical outcomes. However, these reported models and their associated electrostatic potential maps represent an unknown admixture of conformations stemming from the underlying energy landscape of the spike protein. As for any protein, some of the spike's conformational motions are expected to be biophysically relevant, but cannot be interpreted only by static models. Using experimental cryo-EM images, we present the energy landscape of the spike protein conformations, and identify molecular rearrangements along the most-likely conformational path in the vicinity of the open (so called 1RBD-up) state. The resulting global and local atomic refinements reveal larger movements than those expected by comparing the reported 1RBD-up and 1RBD-down cryo-EM models. Here we report greater degrees of "openness" in global conformations of the 1RBD-up state, not revealed in the single-model interpretations of the density maps, together with conformations that overlap with the reported models. We discover how the glycan shield contributes to the stability of these conformations along the minimum free-energy pathway. A local analysis of seven key binding pockets reveals that six out them, including those for engaging ACE2, therapeutic mini-proteins, linoleic acid, two different kinds of antibodies, and protein-glycan interaction sites, switch conformations between their known apo- and holo-conformations, even when the global spike conformation is 1RBD-up. This is reminiscent of a conformational pre-equilibrium. We found only one binding pocket, namely antibody AB-C135 to remain closed along the entire minimum free energy path, suggesting an induced fit mechanism for this enzyme.

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Section: Resultsmentioning

confidence: 99%