Editorial: Understanding Protein Dynamics, Binding and Allostery for Drug Design

Hu, Guang; Doruker, Pemra; Li, Hongchun; Akten, Ebru Demet

doi:10.3389/fmolb.2021.681364

Cited by 6 publications

(2 citation statements)

References 14 publications

(14 reference statements)

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“…Beyond the knowledge gap in our understanding of non-native state conformations or intrinsically disordered proteins (IDPs), the connections of nonnative structures and their kinetic pathways are essential for improving the efficacy of drug delivery, 7 preventing diseases, 8 and guiding discovery of new treatments. 9 To gain insight into these structures and the kinetic pathways connecting them, molecular models and simulations are useful to bridge gaps in experimental structural characterizations.…”

Section: Introductionmentioning

confidence: 99%

“…However, in vivo , proteins are subjected to various environmental stimuli that drive structures away from equilibrium, such as changes in pH, temperature, or ion concentrations that can perturb or tune desired cellular functions. , Understanding protein structural dynamics in response to these environmental signals is paramount to elucidating functional mechanisms. Beyond the knowledge gap in our understanding of non-native state conformations or intrinsically disordered proteins (IDPs), the connections of non-native structures and their kinetic pathways are essential for improving the efficacy of drug delivery, preventing diseases, and guiding discovery of new treatments . To gain insight into these structures and the kinetic pathways connecting them, molecular models and simulations are useful to bridge gaps in experimental structural characterizations.…”

Section: Introductionmentioning

confidence: 99%

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Resolving Dynamics in the Ensemble: Finding Paths through Intermediate States and Disordered Protein Structures

et al. 2021

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Proteins have been found to inhabit a diverse set of threedimensional structures. The dynamics that govern protein interconversion between structures happen over a wide range of time scalespicoseconds to seconds. Our understanding of protein functions and dynamics is largely reliant upon our ability to elucidate physically populated structures. From an experimental structural characterization perspective, we are often limited to measuring the ensemble-averaged structure both in the steady-state and time-resolved regimes. Generating kinetic models and understanding protein structure−function relationships require atomistic knowledge of the populated states in the ensemble. In this Perspective, we present ensemble refinement methodologies that integrate time-resolved experimental signals with molecular dynamics models. We first discuss integration of experimental structural restraints to molecular models in disordered protein systems that adhere to the principle of maximum entropy for creating a complete set of ensemble structures. We then propose strategies to find kinetic pathways between the refined structures, using time-resolved inputs to guide molecular dynamics trajectories and the use of inference to generate tailored stimuli to prepare a desired ensemble of protein states.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Resolving Dynamics in the Ensemble: Finding Paths through Intermediate States and Disordered Protein Structures

et al. 2021

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The role of Wnt palmitoleylated loop conserved disulfide bonds in Wnt-frizzled complex structural dynamics: Insights from molecular dynamics simulations

Dehghanbanadaki,

Mehralitabar,

Sotoudeh

et al. 2023

Computers in Biology and Medicine

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Unlocking the unfolded structure of ubiquitin: Combining time-resolved x-ray solution scattering and molecular dynamics to generate unfolded ensembles

Nijhawan,

Leshchev,

Hsu

et al. 2024

The Journal of Chemical Physics

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The unfolding dynamics of ubiquitin were studied using a combination of x-ray solution scattering (XSS) and molecular dynamics (MD) simulations. The kinetic analysis of the XSS ubiquitin signals showed that the protein unfolds through a two-state process, independent of the presence of destabilizing salts. In order to characterize the ensemble of unfolded states in atomic detail, the experimental XSS results were used as a constraint in the MD simulations through the incorporation of x-ray scattering derived potential to drive the folded ubiquitin structure toward sampling unfolded states consistent with the XSS signals. We detail how biased MD simulations provide insight into unfolded states that are otherwise difficult to resolve and underscore how experimental XSS data can be combined with MD to efficiently sample structures away from the native state. Our results indicate that ubiquitin samples unfolded in states with a high degree of loss in secondary structure yet without a collapse to a molten globule or fully solvated extended chain. Finally, we propose how using biased-MD can significantly decrease the computational time and resources required to sample experimentally relevant nonequilibrium states.

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Editorial: Understanding Protein Dynamics, Binding and Allostery for Drug Design

Cited by 6 publications

References 14 publications

Resolving Dynamics in the Ensemble: Finding Paths through Intermediate States and Disordered Protein Structures

Resolving Dynamics in the Ensemble: Finding Paths through Intermediate States and Disordered Protein Structures

The role of Wnt palmitoleylated loop conserved disulfide bonds in Wnt-frizzled complex structural dynamics: Insights from molecular dynamics simulations

Unlocking the unfolded structure of ubiquitin: Combining time-resolved x-ray solution scattering and molecular dynamics to generate unfolded ensembles

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