Assessment of the model refinement category in CASP12

We here report on the assessment of the model refinement predictions submitted to the 12th Experiment on the Critical Assessment of Protein Structure Prediction (CASP12). This is the fifth refinement experiment since CASP8 (2008) and, as with the previous experiments, the predictors were invited to refine selected server models received in the regular (nonrefinement) stage of the CASP experiment. We assessed the submitted models using a combination of standard CASP measures. The coefficients for the linear combination of Z‐scores (the CASP12 score) have been obtained by a machine learning algorithm trained on the results of visual inspection. We identified eight groups that improve both the backbone conformation and the side chain positioning for the majority of targets. Albeit the top methods adopted distinctively different approaches, their overall performance was almost indistinguishable, with each of them excelling in different scores or target subsets. What is more, there were a few novel approaches that, while doing worse than average in most cases, provided the best refinements for a few targets, showing significant latitude for further innovation in the field.

[1]  G. Hummer,et al.  Are current molecular dynamics force fields too helical? , 2008, Biophysical journal.

[2]  A. Cavalli,et al.  Investigating drug-target association and dissociation mechanisms using metadynamics-based algorithms. , 2015, Accounts of chemical research.

[3]  Prasanna R Kolatkar,et al.  Assessment of CASP7 structure predictions for template free targets , 2007, Proteins.

[4]  Vincent B. Chen,et al.  Correspondence e-mail: , 2000 .

[5]  Chaok Seok,et al.  Simultaneous refinement of inaccurate local regions and overall structure in the CASP12 protein model refinement experiment , 2018, Proteins.

[6]  David T Jones,et al.  Evaluation of predictions in the CASP10 model refinement category , 2013, Proteins.

[7]  B. L. de Groot,et al.  CHARMM36m: an improved force field for folded and intrinsically disordered proteins , 2016, Nature Methods.

[8]  W. L. Jorgensen,et al.  Improved Peptide and Protein Torsional Energetics with the OPLS-AA Force Field , 2015, Journal of chemical theory and computation.

[9]  Roland L Dunbrack,et al.  Assessment of refinement of template‐based models in CASP11 , 2016, Proteins.

[10]  Francesco Luigi Gervasio,et al.  New advances in metadynamics , 2012 .

[11]  C Venclovas,et al.  Processing and analysis of CASP3 protein structure predictions , 1999, Proteins.

[12]  Kliment Olechnovič,et al.  CAD‐score: A new contact area difference‐based function for evaluation of protein structural models , 2013, Proteins.

[13]  R. Dror,et al.  How Fast-Folding Proteins Fold , 2011, Science.

[14]  Chaok Seok,et al.  Effective protein model structure refinement by loop modeling and overall relaxation , 2016, Proteins.

[15]  Stefano Piana,et al.  Refinement of protein structure homology models via long, all‐atom molecular dynamics simulations , 2012, Proteins.

[16]  Torsten Schwede,et al.  Assessment of template based protein structure predictions in CASP9 , 2011, Proteins.

[17]  Edward W. Lowe,et al.  Computational Methods in Drug Discovery , 2014, Pharmacological Reviews.

[18]  Keehyoung Joo,et al.  Refinement of protein termini in template‐based modeling using conformational space annealing , 2011, Proteins.

[19]  Jimin Pei,et al.  An automatic method for CASP9 free modeling structure prediction assessment , 2011, Bioinform..

[20]  A. Valencia,et al.  From residue coevolution to protein conformational ensembles and functional dynamics , 2015, Proceedings of the National Academy of Sciences.

[21]  P. Bradley,et al.  High-resolution structure prediction and the crystallographic phase problem , 2007, Nature.

[22]  Hongyi Zhou,et al.  Distance‐scaled, finite ideal‐gas reference state improves structure‐derived potentials of mean force for structure selection and stability prediction , 2002, Protein science : a publication of the Protein Society.

[23]  Stefano Piana,et al.  Demonstrating an Order-of-Magnitude Sampling Enhancement in Molecular Dynamics Simulations of Complex Protein Systems. , 2016, Journal of chemical theory and computation.

[24]  Michael Levitt,et al.  Consistent refinement of submitted models at CASP using a knowledge‐based potential , 2010, Proteins.

[25]  R. Dror,et al.  Improved side-chain torsion potentials for the Amber ff99SB protein force field , 2010, Proteins.

[26]  Yang Zhang Protein structure prediction: when is it useful? , 2009, Current opinion in structural biology.

[27]  Michael Feig,et al.  What makes it difficult to refine protein models further via molecular dynamics simulations? , 2018, Proteins.

[28]  Joseph A Morrone,et al.  Advances in free-energy-based simulations of protein folding and ligand binding. , 2016, Current opinion in structural biology.

[29]  Dennis Della Corte,et al.  Protein structure refinement with adaptively restrained homologous replicas , 2016, Proteins.

[30]  Alexander D. MacKerell,et al.  Optimization of the additive CHARMM all-atom protein force field targeting improved sampling of the backbone φ, ψ and side-chain χ(1) and χ(2) dihedral angles. , 2012, Journal of chemical theory and computation.

[31]  Vahid Mirjalili,et al.  Physics‐based protein structure refinement through multiple molecular dynamics trajectories and structure averaging , 2014, Proteins.

[32]  C. Simmerling,et al.  ff14SB: Improving the Accuracy of Protein Side Chain and Backbone Parameters from ff99SB. , 2015, Journal of chemical theory and computation.

[33]  Adam Zemla,et al.  LGA: a method for finding 3D similarities in protein structures , 2003, Nucleic Acids Res..

[34]  R. Samudrala,et al.  An all-atom distance-dependent conditional probability discriminatory function for protein structure prediction. , 1998, Journal of molecular biology.

[35]  Yang Zhang,et al.  Automated protein structure modeling in CASP9 by I‐TASSER pipeline combined with QUARK‐based ab initio folding and FG‐MD‐based structure refinement , 2011, Proteins.

[36]  Krzysztof Fidelis,et al.  CASP prediction center infrastructure and evaluation measures in CASP10 and CASP ROLL , 2014, Proteins.

[37]  Krzysztof Fidelis,et al.  CASP11 statistics and the prediction center evaluation system , 2016, Proteins.

[38]  Anna Tramontano,et al.  Evaluating the usefulness of protein structure models for molecular replacement , 2005, ECCB/JBI.

[39]  Vahid Mirjalili,et al.  Protein structure refinement via molecular‐dynamics simulations: What works and what does not? , 2016, Proteins.

[40]  Frank DiMaio,et al.  CASP11 refinement experiments with ROSETTA , 2016, Proteins.

[41]  Vahid Mirjalili,et al.  Protein Structure Refinement through Structure Selection and Averaging from Molecular Dynamics Ensembles. , 2013, Journal of chemical theory and computation.

[42]  J. Skolnick,et al.  A distance‐dependent atomic knowledge‐based potential for improved protein structure selection , 2001, Proteins.

[43]  Matthew P Jacobson,et al.  Assessment of protein structure refinement in CASP9 , 2011, Proteins.

[44]  K. Dill,et al.  Assessment of the protein‐structure refinement category in CASP8 , 2009, Proteins.

[45]  Jooyoung Lee,et al.  A Simple and Efficient Protein Structure Refinement Method. , 2017, Journal of chemical theory and computation.

[46]  Christodoulos A Floudas,et al.  Princeton_TIGRESS: Protein geometry refinement using simulations and support vector machines , 2014, Proteins.

[47]  Raphael Nudelman,et al.  An integrated in silico 3D model-driven discovery of a novel, potent, and selective amidosulfonamide 5-HT1A agonist (PRX-00023) for the treatment of anxiety and depression. , 2006, Journal of medicinal chemistry.