Simulation of FRET dyes allows quantitative comparison against experimental data

Reinartz, Ines; Sinner, Claude; Nettels, Daniel; Stucki-Buchli, Brigitte; Stockmar, Florian; Panek, Paweł T.; Jacob, Christoph R.; Nienhaus, G. Ulrich; Schuler, Benjamin; Schug, Alexander

doi:10.1063/1.5010434

Cited by 39 publications

(40 citation statements)

References 69 publications

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“…Other methods do not directly provide structural information but have first to be carefully interpreted (e.g. small-angle scattering (SAXS) [7] or Fluorescence Resonance Energy Transfer (FRET) [8]). Yet in spite of considerable progress of experimental techniques, the number of structurally resolved RNA structures collected in public databases [9,10] is still small due to experimental limitations and considerably lags the number of known sequences.…”

Section: Introductionmentioning

confidence: 99%

Evaluating DCA-based method performances for RNA contact prediction by a well-curated dataset

Pucci

Zerihun

Peter

et al. 2019

Preprint

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AbstractRNA molecules play many pivotal roles in the cellular functioning that are still not fully understood. Any detailed understanding of RNA function requires knowledge of its three-dimensional structure, yet experimental RNA structure resolution remains demanding. Recent advances in sequencing provide unprecedented amounts of sequence data that can be statistically analysed by methods such as Direct Coupling Analysis (DCA) to determine spatial proximity or contacts of specific nucleic acid pairs, which improve the quality of structure prediction. To quantify this structure prediction improvement, we here present a well curated dataset of about seventy RNA structures with high resolution and compare different nucleotide-nucleotide contact prediction methods available in the literature. We observe only minor difference between the performances of the different methods. Moreover, we discuss how these predictions are robust for different contact definitions and how strongly depend on procedures used to curate and align the families of homologous RNA sequences.

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Section: Introductionmentioning

confidence: 99%

Evaluating DCA-based method performances for RNA contact prediction by a well-curated dataset

Pucci

Zerihun

Peter

et al. 2019

Preprint

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“…Complementary, we perform unbiased and biased all-atom MD simulations of the full dimer in a physiological NaCl solution and loadings of different nucleotides (total simulation length of 25 µs) to obtain insights into molecular mechanisms which are not directly accessible with smFRET. [36][37][38][39] We find that Arg380, which has been assumed to be involved in the functional cycle before, [40][41][42] is a prominent residue for the transfer of allosteric information from the nucleotide binding site to the full protein. Finally, we experimentally investigate both the time-and length scales of allosteric communication identified from MD simulations.…”

Section: Introductionmentioning

confidence: 82%

Hierarchical coupling between ATP hydrolysis and Hsp90’s client binding site

Wolf

Sohmen

Hellenkamp

et al. 2020

Preprint

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I.ABSTRACTSeveral indicators for a signal propagation from a binding site to a distant functional site have been found in the Hsp90 dimer. Here we determined a time-resolved pathway from ATP hydrolysis to changes in a distant folding substrate binding site. This was possible by combining single-molecule fluorescence-based methods with extensive atomistic nonequilibrium molecular dynamics simulations. We find that hydrolysis of one ATP effects a structural asymmetry in the full Hsp90 dimer that leads to the collapse of a central folding substrate binding site. Arg380 is the major mediator in transferring structural information from the nucleotide to the substrate binding site. This allosteric process occurs via hierarchical dynamics that involve timescales from picoto milliseconds and length scales from Ångstroms to several nanometers. We presume that similar hierarchical mechanisms are fundamental for information transfer through many other proteins.

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“…S3 Appendix and S4 Appendix). After verifying sufficient exchange rates in short REX simulations (every 1000 steps, rate ≈ 16%), the sigmoid potential based on Eq (7) was provided as a look-up table. Each simulation run for 250ns with a stepsize of 2f s on 60 (Trp-Cage) and 100 (Villin headpiece) replica.…”

Section: Setup Of Rex MD Simulationsmentioning

confidence: 99%

“…In contrast, experimental structure determination with methods such as X-ray crystallography or NMR spectroscopy are comparably time-consuming and expensive with often involved procedures. Some other experimental techniques, e.g., SAXS, FRET, or cryoEM, do not directly provide structural data but have to be carefully interpreted [6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Refinement of protein structure via contact based potentials in replica exchange simulations

Schug

Weiel

Voronin

2020

Preprint

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Proteins are complex biomolecules which perform critical tasks in living organisms. Knowledge of a protein's structure is essential for understanding its physiological function in detail. Despite the incredible progress in experimental techniques, protein structure determination is still expensive, time-consuming, and arduous. That is why computer simulations are often used to complement or interpret experimental data. Here, we explore how in silico protein structure determination based on replica exchange molecular dynamics can benefit from including contact information derived from theoretical and experimental sources, such as direct coupling analysis or NMR spectroscopy. To reflect the influence from erroneous and noisy data we probe how false-positive contacts influence the simulated ensemble. Specifically, we integrate varying numbers of randomly selected native and non-native contacts and explore how such a bias can guide simulations towards the native state. We investigate the number of contacts needed for a significant enrichment of native-like conformations and show the capabilities and limitations of this method. Adhering to a threshold of approximately 75% true-positive contacts within a simulation, we obtain an ensemble with native-like conformations of high quality. We find that contact-guided REX MD is capable of delivering physically reasonable models of a protein's structure. Author summaryProtein structure prediction, that is obtaining a protein structure starting from a sequence using any computational method, is a great challenge. Over the past years a broad variety of methods evolved, ranging from algorithms for "blind" or de novo predictions using Monte-Carlo or physics-based biomolecular simulation methods to algorithms transferring structure information obtained from known homologous proteins. Recently, purely data-driven approaches using neural networks have shown to be capable of predicting high-quality structures. However, some local structural motifs are only poorly resolved and need further refinement. Here, we explore to what extent contact information helps guiding replica exchange molecular dynamics towards the native fold. By adding a contact pair bias potential to the energy function, we effectively guide the search towards the target structure by narrowing the conformational space to be sampled. We find that such an energetic bias, even if containing false-positive contacts to a certain extent, greatly enhances the refinement process and improves the chance of finding the native state in a single run.

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Simulation of FRET dyes allows quantitative comparison against experimental data

Cited by 39 publications

References 69 publications

Evaluating DCA-based method performances for RNA contact prediction by a well-curated dataset

Evaluating DCA-based method performances for RNA contact prediction by a well-curated dataset

Hierarchical coupling between ATP hydrolysis and Hsp90’s client binding site

Refinement of protein structure via contact based potentials in replica exchange simulations

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