Elucidating Molecular Motion through Structural and Dynamic Filters of Energy-Minimized Conformer Ensembles

Emani, Prashant S.; Bardaro, Michael F.; Huang, Wei; Aragón, Sergio R.; Varani, Gabriele; Drobny, Gary P.

doi:10.1021/jp409386t

Cited by 7 publications

(16 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…By contrast, a sample-and-select procedure can identify a parsimonious set of distinct conformational substates from a large pool of sampled conformers by matching back-calculated RDCs to measured ones 52,53 . In one example, this approach identified one major and two minor conformational substates sampled with accelerated MD in the protein SH3C from CD2AP’s free-energy landscape from a large set of RDC measurements, and established a hierarchy of motions and states 54 .…”

Section: Solution Nmr Signals Are Generated By Multiple Conformationsmentioning

confidence: 99%

Integrative, dynamic structural biology at atomic resolution—it's about time

Bedem¹,

Fraser²

2015

Nat Methods

233

171

View full text Add to dashboard Cite

Biomolecules adopt a dynamic ensemble of conformations, each with the potential to interact with binding partners or perform the chemical reactions required for a multitude of cellular functions. Recent advances in X-ray crystallography, Nuclear Magnetic Resonance (NMR) spectroscopy, and other techniques are helping us realize the dream of seeing—in atomic detail—how different parts of biomolecules exchange between functional sub-states using concerted motions. Integrative structural biology has advanced our understanding of the formation of large macromolecular complexes and how their components interact in assemblies by leveraging data from many low-resolution methods. Here, we review the growing opportunities for integrative, dynamic structural biology at the atomic scale, contending there is increasing synergistic potential between X-ray crystallography, NMR, and computer simulations to reveal a structural basis for protein conformational dynamics at high resolution.

show abstract

Section: Solution Nmr Signals Are Generated By Multiple Conformationsmentioning

confidence: 99%

Integrative, dynamic structural biology at atomic resolution—it's about time

Bedem¹,

Fraser²

2015

Nat Methods

233

171

View full text Add to dashboard Cite

show abstract

“…More recently the combined solution/solid-state data have been used to construct an ensemble of TAR structures [169]. In this approach, RDCs were used to filter an initial set of 500 ROSETTA energy-minimized TAR structures, yielding a set of five structures.…”

Section: Nmr Studies Of the Dynamics Of Biomolecular Conformationamentioning

confidence: 99%

“…A comparison of the results obtained using the five-member ensemble [169] with those of the twenty-member ensemble [53, 164] revealed excellent agreement in angles spanned by the two helical domains. However, bulge conformations obtained from the two ensembles differed significantly [169].…”

Section: Nmr Studies Of the Dynamics Of Biomolecular Conformationamentioning

confidence: 99%

“…However, bulge conformations obtained from the two ensembles differed significantly [169]. It is possible that the discrepancy arises from the limited size of the initial pool of energy-minimized structures and/or from the assumption, in the GE theory, of a coincidence of the rotational diffusion tensors at the instant of exchange.…”

Section: Nmr Studies Of the Dynamics Of Biomolecular Conformationamentioning

confidence: 99%

See 1 more Smart Citation

NMR studies of dynamic biomolecular conformational ensembles

Torchia

2015

Progress in Nuclear Magnetic Resonance Spectroscopy

View full text Add to dashboard Cite

Multidimensional heteronuclear NMR approaches can provide nearly complete sequential signal assignments of isotopically enriched biomolecules. The availability of assignments together with measurements of spin relaxation rates, residual spin interactions, J-couplings and chemical shifts provides information at atomic resolution about internal dynamics on timescales ranging from ps to ms, both in solution and in the solid state. However, due to the complexity of biomolecules, it is not possible to extract a unique atomic-resolution description of biomolecular motions even from extensive NMR data when many conformations are sampled on multiple timescales. For this reason, powerful computational approaches are increasingly applied to large NMR data sets to elucidate conformational ensembles sampled by biomolecules. In the past decade, considerable attention has been directed at an important class of biomolecules that function by binding to a wide variety of target molecules. Questions of current interest are: “Does the free biomolecule sample a conformational ensemble that encompasses the conformations found when it binds to various targets; and if so, on what time scale is the ensemble sampled?” This article reviews recent efforts to answer these questions, with a focus on comparing ensembles obtained for the same biomolecules by different investigators. A detailed comparison of results obtained is provided for three biomolecules: ubiquitin, calmodulin and the HIV-1 trans-activation response RNA.

show abstract

“…Recently, hybrid experimental-computational approaches have been developed that enable the determination of dynamic ensembles of biomolecules at atomic resolution [10][11][12][13][14][15] . The ensembles describe the different conformations sampled by a given biomolecule in solution.…”

mentioning

confidence: 99%

High Performance Virtual Screening by Targeting a High-resolution RNA Dynamic Ensemble

Ganser

Lee

Sathyamoorthy

et al. 2017

Preprint

View full text Add to dashboard Cite

2Dynamic ensembles that capture the flexibility of RNA three-dimensional (3D) structures hold great promise in advancing RNA-targeted drug discovery. Here, we experimentally screened the transactivation response element (TAR) RNA from human immunodeficiency virus type-1 (HIV-1) against ~100,000 small molecules. We used this dataset, along with 240 known hit molecules, to evaluate virtual screening (VS) against a high-resolution TAR ensemble determined by combining NMR spectroscopy and molecular dynamics (MD) simulations. Ensemble-based VS (EBVS) scores molecules with an area under the receiver operator characteristic curve (ROC AUC) of 0.87 with ~50% of all hits falling within the top 2% of scored molecules, and also correctly predicts the different TAR inter-helical structures when bound to six molecules. The prediction accuracy decreased significantly with decreasing accuracy of the target ensemble or when docking against a single RNA structure. These results demonstrate that experimentally determined ensembles can significantly enrich libraries with structure-specific RNA binders as well as motivate the continued development of methods for improving ensemble accuracy.Accompanying the non-coding RNA (ncRNA) revolution has been growing interest in RNA as a drug target, particularly for diseases that do not have suitable protein targets [1][2][3][4][5][6] . The growing list of ncRNA targets now includes microRNAs, long ncRNAs, repetitive RNA transcripts, riboswitches, and viral RNAs. Much attention has been directed towards targeting ncRNAs with small molecules, which do not suffer from the inherent delivery limitations associated with oligonucleotide-based therapeutics, and which can be tailored to specifically target the diverse 3D structures of RNA 2-5 . There are, however, fundamental challenges in targeting RNA using small molecules [4][5][6][7] . Libraries used in highthroughput screening (HTS) are optimized for the deep, hydrophobic pockets of protein targets and not the more polar and solvent exposed pockets typical of RNA targets 7 . Screens targeting ncRNAs typically yield very few hit molecules most of which show little discrimination against other cellular RNAs, have unfavorable pharmacological properties, and poor activity in cell-based assays. Rational . CC-BY-NC-ND 4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/151407 doi: bioRxiv preprint first posted online 3 approaches to identify small molecules that bind specific RNA secondary structure have had some 19,20 . EBVS was able to score a small set of 38 known TAR binders with an accuracy comparable to that obtained when docking 48 small molecules to their known bound RNA structure 9 . Experimentally testing the top 57 scoring small molecules out of a screen of 51,000 compounds yielded six hit molecules that bind TAR in vitro, including the first example of a small molecule that binds an RNA apical loop, and a highly ...

show abstract

Elucidating Molecular Motion through Structural and Dynamic Filters of Energy-Minimized Conformer Ensembles

Cited by 7 publications

References 68 publications

Integrative, dynamic structural biology at atomic resolution—it's about time

Integrative, dynamic structural biology at atomic resolution—it's about time

NMR studies of dynamic biomolecular conformational ensembles

High Performance Virtual Screening by Targeting a High-resolution RNA Dynamic Ensemble

Contact Info

Product

Resources

About