Blind protein structure prediction using accelerated free-energy simulations

Pérez, Alberto; Morrone, Joseph A.; Brini, Emiliano; MacCallum, Justin L.; Dill, Ken A.

doi:10.1126/sciadv.1601274

Cited by 63 publications

(81 citation statements)

References 43 publications

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“…Like in the examples above, most top models do not list templates in their PARENT records; however, if they did employ templates, then they have dealt with removal of these insertions and repacking quite successfully. Laufer_seed uses extensive molecular dynamics sampling from server models, a very innovative technique relying largely on fundamental physics principles that helped to correctly model the different insertions. Compared to the best server among the four that feed Laufer_seed, its top prediction for T0868D1 is 10 GDTTS units better (possibly even more if another server was used for model seeding).…”

Section: Resultsmentioning

confidence: 99%

Assessment of hard target modeling in CASP12 reveals an emerging role of alignment‐based contact prediction methods

et al. 2017

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We present our assessment of CASP12 modeling efforts for targets with no obvious templates of high sequence/structure similarity in the PDB, that is for evaluation units of the free modeling (FM) and free modeling/template‐based modeling (FM/TBM) categories. Models were clustered and ranked using the Global Distance Test‐Total Score and 5 additional metrics developed in previous CASP rounds, producing short lists of models that were subject to visual inspection in comparison to the target structures. The whole procedure was implemented as a web app that facilitates model selection and visual inspection, and could become useful to facilitate and standardize future assessments. We describe cases of (1) targets with remarkably good predictions, (2) targets whose models captured some global shape and topology features, and (3) targets for which models fail to capture even coarse features. We note that despite this CASP being among the most challenging ones, a measurable improvement of the top predictions is apparent, that we attribute to the emergence of accurate contact prediction methods and the increased number of available sequences. We also briefly discuss current limitations in tertiary structure prediction exemplified by CASP12 targets. Overall, the Baker, Zhang, and Lee manual groups and servers were identified as the top global performing groups.

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Section: Resultsmentioning

confidence: 99%

Assessment of hard target modeling in CASP12 reveals an emerging role of alignment‐based contact prediction methods

et al. 2017

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“…This size, ~40 kDa, is at the limits of NMR, and beyond the limits of MD. The largest protein previously folded by MD without data is just over 100 residues, and MELDxMD has only been able to fold proteins up to 240 residues, with the aid of experimental data . There are only ~50 NMR structures currently in the PDB larger than this.…”

Section: Resultsmentioning

confidence: 99%

“…In this way, no information is ever lost and detailed balance is always obeyed—vital for a physics based methodology. Restraints follow our previously developed MELD protocol …”

Section: Methodsmentioning

confidence: 99%

“…Restraints follow our previously developed MELD protocol. 5,6,21 Each simulation was started from server templates and ran for several days. To improve sampling and compensate for the low exchange probabilities in the REMD ladder, we scored the ensembles based on all the provided peaks that did not have ambiguous contacts.…”

Section: Meldxmd Simulation Protocolmentioning

confidence: 99%

“…The largest protein previously folded by MD without data is just over 100 residues, 27 and MELDxMD has only been able to fold proteins up to 240 residues, with the aid of experimental data. 21 There are only~50 NMR structures currently in the PDB larger than this. However, MELDxMD was able to leverage the NMR data to explore near-native conformations and it generated five reasonable structures (TM score 0.64-0.68).…”

Section: What Went Right?mentioning

confidence: 99%

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NMR‐assisted protein structure prediction with MELDxMD

et al. 2019

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We describe the performance of MELD‐accelerated molecular dynamics (MELDxMD) in determining protein structures in the NMR‐data‐assisted category in CASP13. Seeded from web server predictions, MELDxMD was found best in the NMR category, over 17 targets, outperforming the next‐best groups by a factor of ~4 in z‐score. MELDxMD gives ensembles, not single structures; succeeds on a 326‐mer, near the current upper limit for NMR structures; and predicts structures that match experimental residual dipolar couplings even though the only NMR‐derived data used in the simulations was NOE‐based ambiguous atom–atom contacts and backbone dihedrals. MELD can use noisy and ambiguous experimental information to reduce the MD search space. We believe MELDxMD is a promising method for determining protein structures from NMR data.

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High Accuracy Protein Structures from Minimal Sparse Paramagnetic Solid‐State NMR Restraints

et al. 2019

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There is apressing need for new computational tools to integrate data from diverse experimental approaches in structural biology.W ep resent as trategy that combines sparse paramagnetic solid-state NMR restraints with physics-based atomistic simulations.O ur approach explicitly accounts for uncertainty in the interpretation of experimental data through the use of as emi-quantitative mapping between the data and the restraint energy that is calibrated by extensive simulations. We apply our approach to solid-state NMR data for the model protein GB1 labeled with Cu 2+ -EDTAatsix different sites.W e are able to determine the structure to 0.9 accuracy within asingle dayofcomputation on aGPU cluster.Wefurther show that in some cases,the data from only asingle paramagnetic tag are sufficient for accurate folding.Supportinginformation and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.

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Blind protein structure prediction using accelerated free-energy simulations

Abstract: Protein structures can be predicted by combining atomistic simulations and coarse information.

Cited by 63 publications

References 43 publications

Assessment of hard target modeling in CASP12 reveals an emerging role of alignment‐based contact prediction methods

Assessment of hard target modeling in CASP12 reveals an emerging role of alignment‐based contact prediction methods

NMR‐assisted protein structure prediction with MELDxMD

High Accuracy Protein Structures from Minimal Sparse Paramagnetic Solid‐State NMR Restraints

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