Visualizing ensembles in structural biology

Melvin, Ryan L.; Salsbury, Freddie R.

doi:10.1016/j.jmgm.2016.05.001

Cited by 22 publications

(41 citation statements)

References 77 publications

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“…46 Images of structures from the most populated cluster of each configuration (Figure 6) were produced using a visual statistics package, where the shadows represent one standard deviation of RMSD for that cluster with the median structure colored by secondary structure. 47 …”

Section: Methodsmentioning

confidence: 99%

Binding Site Configurations Probe the Structure and Dynamics of the Zinc Finger of NEMO (NF-κB Essential Modulator)

et al. 2017

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Zinc-finger proteins are regulators of critical signaling pathways for various cellular functions, including apoptosis and oncogenesis. Here, we investigate how binding site protonation states and zinc coordination influence protein structure, dynamics, and ultimately function, as these pivotal regulatory proteins are increasingly important for protein engineering and therapeutic discovery. To better understand the thermodynamics and dynamics of the zinc finger of NEMO (NF-κB essential modulator), as well as the role of zinc, we present results of 20 μs molecular dynamics trajectories, 5 μs for each of four active site configurations. Consistent with experimental evidence, the zinc ion is essential for mechanical stabilization of the functional, folded conformation. Hydrogen bond motifs are unique for deprotonated configurations yet overlap in protonated cases. Correlated motions and principal component analysis corroborate the similarity of the protonated configurations and highlight unique relationships of the zinc-bound configuration. We hypothesize a potential mechanism for zinc binding from results of the thiol configurations. The deprotonated, zinc-bound configuration alone predominantly maintains its tertiary structure throughout all 5 μs and alludes rare conformations potentially important for (im)proper zinc-finger-related protein–protein or protein–DNA interactions.

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Section: Methodsmentioning

confidence: 99%

Binding Site Configurations Probe the Structure and Dynamics of the Zinc Finger of NEMO (NF-κB Essential Modulator)

et al. 2017

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“…The central structure of the cluster is highlighted in color and shown as opaque. 31 All structures are aligned together using CE alignment to show the structural variance of the predicted ensemble.…”

Section: Methodsmentioning

confidence: 99%

Protein Folding and Structure Prediction from the Ground Up II: AAWSEM for α/β Proteins

Chen

Lin

et al. 2016

J. Phys. Chem. B

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The atomistic associative memory, water mediated, structure and energy model (AAWSEM) is an efficient coarse-grained force field with transferable tertiary interactions that incorporates local in sequence energetic biases using structural information derived from all-atom simulations of long segments of the protein. For α helical proteins, the accuracy of structure prediction using AAWSEM has been established previously. In this article, we examine the capability of AAWSEM to predict the structure of α/β proteins. We also elaborate on an iterative approach that uses the structures from a first round of AAWSEM simulation as fragment memories. This iterative scheme improves the quality of the structure prediction and makes the free energy profile more funneled toward native configurations. We explore the use of clustering analyses as a way of evaluating the confidence in various structure prediction models. Clustering using a local relative order parameter (mutual Q) of the predicted structural ensemble turns out to be optimal. The tightest cluster according to mutual Q generally has the most correctly folded structure. Since there is no bioinformatic input, AAWSEM amounts to an ab initio protein structure prediction method that combines the efficiency of coarse-grained simulations with the local structural accuracy that can be achieved from all-atom simulations.

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“…45 Frame selection was based on quality threshold clustering and statistical analysis as previously detailed. 46 The additional structures in the Supporting Information are all frames within one “modified standard deviation” 46 of the representative structure as assigned by the Quality Threshold (QT) 37 algorithm in VMD. Our scripts for producing such figures are available online via figshare.…”

Section: Methodsmentioning

confidence: 99%

All-Atom Molecular Dynamics Reveals Mechanism of Zinc Complexation with Therapeutic F10

2016

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Advancing the use of therapeutic nucleic acids requires understanding the chemical and structural properties that allow these polymers to promote the death of malignant cells. Here we explore Zn2+ complexation by the fluoropyrimidine polymer F10, which has strong activities in multiple preclinical models of cancer. Delivery of fluoropyrimidine FdUMP in the 10-residue polymer F10 rather than the nucleobase (5-fluorouracil) allows consideration of metal ion binding effects on drug delivery. The differences in metal ion interactions with fluoropyrimidine compared to normal DNA results in conformation changes that affect protein binding, cell uptake, and codelivery of metals such as zinc, and the cytoxicity thereof. Microsecond-time-scale, all-atom simulations of F10 predict that zinc selectively stabilizes the polymer via interactions with backbone phosphate groups and suggest a mechanism of complexation for the zinc-base interactions shown in previous experimental work. The positive zinc ions are attracted to the negatively charged phosphate groups. Once the Zn2+ ions are near F10, they cause the base’s N3 nitrogen to deprotonate. Subsequently, magnesium atoms displace zinc from their interactions with phosphate, freeing the zinc ions to interact with the FdU bases by forming weak interactions with the O4 oxygen and the fluorine attached to C5. These interactions of magnesium with phosphate groups and zinc with nucleobases agree with previous experimental results and are seen in MD simulations only when magnesium is introduced after N3 deprotonation, indicating a specific order of metal binding events. Additionally, we predict interactions between zinc and F10’s O2 atoms, which were not previously observed. By comparison to 10mers of polyU and polydT, we also predict that the presence of fluorine increases the binding affinity of zinc to F10 relative to analogous strands of RNA and DNA consisting of only native nucleotides.

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Visualizing ensembles in structural biology

Cited by 22 publications

References 77 publications

Binding Site Configurations Probe the Structure and Dynamics of the Zinc Finger of NEMO (NF-κB Essential Modulator)

Binding Site Configurations Probe the Structure and Dynamics of the Zinc Finger of NEMO (NF-κB Essential Modulator)

Protein Folding and Structure Prediction from the Ground Up II: AAWSEM for α/β Proteins

All-Atom Molecular Dynamics Reveals Mechanism of Zinc Complexation with Therapeutic F10

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