Category: Papers

Adaptive Markov state model estimation using short reseeding trajectories.

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In the last decade, advances in molecular dynamics (MD) and Markov State Model (MSM) methodologies have made possible accurate and efficient estimation of kinetic rates and reactive pathways for complex biomolecular dynamics occurring on slow time scales. A promising approach to enhanced sampling of MSMs is to use “adaptive” methods, in which new MD trajectories are “seeded” preferentially from previously identified states. Here, we investigate the performance of various MSM estimators …

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Reconciling simulated ensembles of apomyoglobin with experimental HDX data using Bayesian inference and multi-ensemble Markov State Models.

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Hydrogen/deuterium exchange (HDX) is a powerful technique to investigate protein conformational dynamics at amino acid resolution. Because HDX provides a measurement of solvent exposure of backbone hydrogens, ensemble-averaged over potentially slow kinetic processes, it has been challenging to use HDX protection factors to refine structural ensembles obtained from molecular dynamics simulations. This entails two dual challenges: (1) identifying structural observables that best correlate with ba…

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The Cap-Snatching SFTSV Endonuclease Domain Is an Antiviral Target.

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Severe fever with thrombocytopenia syndrome virus (SFTSV) is a tick-borne virus with 12%-30% case mortality rates and is related to the Heartland virus (HRTV) identified in the United States. Together, SFTSV and HRTV are emerging segmented, negative-sense RNA viral (sNSV) pathogens with potential global health impact. Here, we characterize the amino-terminal cap-snatching endonuclease domain of SFTSV polymerase (L) and solve a 2.4-Å X-ray crystal structure. While th…

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Octanol-water partition coefficient measurements for the SAMPL6 blind prediction challenge.

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Partition coefficients describe the equilibrium partitioning of a single, defined charge state of a solute between two liquid phases in contact, typically a neutral solute. Octanol-water partition coefficients ([Formula: see text]), or their logarithms (log P), are frequently used as a measure of lipophilicity in drug discovery. The partition coefficient is a physicochemical property that captures the thermodynamics of relative solvation between aqueous and nonpolar phases, and the…

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A Small-Molecule Pan-Id Antagonist Inhibits Pathologic Ocular Neovascularization.

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Id helix-loop-helix (HLH) proteins (Id1-4) bind E protein bHLH transcription factors, preventing them from forming active transcription complexes that drive changes in cell states. Id proteins are primarily expressed during development to inhibit differentiation, but they become re-expressed in adult tissues in diseases of the vasculature and cancer. We show that the genetic loss of Id1/Id3 reduces ocular neovascularization in mouse models of wet age-related macular degeneration (AMD) a…

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Cooperative Changes in Solvent Exposure Identify Cryptic Pockets, Switches, and Allosteric Coupling.

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Proteins are dynamic molecules that undergo conformational changes to a broad spectrum of different excited states. Unfortunately, the small populations of these states make it difficult to determine their structures or functional implications. Computer simulations are an increasingly powerful means to identify and characterize functionally relevant excited states. However, this advance has uncovered a further challenge: it can be extremely difficult to identify the most salient feature…

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