CABS-flex predictions of protein flexibility compared with NMR ensembles

Motivation: Identification of flexible regions of protein structures is important for understanding of their biological functions. Recently, we have developed a fast approach for predicting protein structure fluctuations from a single protein model: the CABS-flex. CABS-flex was shown to be an efficient alternative to conventional all-atom molecular dynamics (MD). In this work, we evaluate CABS-flex and MD predictions by comparison with protein structural variations within NMR ensembles. Results: Based on a benchmark set of 140 proteins, we show that the relative fluctuations of protein residues obtained from CABS-flex are well correlated to those of NMR ensembles. On average, this correlation is stronger than that between MD and NMR ensembles. In conclusion, CABS-flex is useful and complementary to MD in predicting protein regions that undergo conformational changes as well as the extent of such changes. Availability and implementation: The CABS-flex is freely available to all users at http://biocomp.chem.uw.edu.pl/CABSflex. Contact: sekmi@chem.uw.edu.pl Supplementary information: Supplementary data are available at Bioinformatics online.

[1]  Sébastien Morin,et al.  Synergistic Applications of MD and NMR for the Study of Biological Systems , 2012, Journal of biomedicine & biotechnology.

[2]  Gert Vriend,et al.  The precision of NMR structure ensembles revisited , 2003, Journal of biomolecular NMR.

[3]  A. Kolinski,et al.  Structural features that predict real‐value fluctuations of globular proteins , 2012, Proteins.

[4]  Guoli Wang,et al.  PISCES: a protein sequence culling server , 2003, Bioinform..

[5]  James O. Wrabl,et al.  The role of protein conformational fluctuations in allostery, function, and evolution. , 2011, Biophysical chemistry.

[6]  Maria A Miteva,et al.  Exploring NMR ensembles of calcium binding proteins: Perspectives to design inhibitors of protein-protein interactions , 2011, BMC Structural Biology.

[7]  Dominik Gront,et al.  Combining Coarse-Grained Protein Models with Replica-Exchange All-Atom Molecular Dynamics , 2013, International journal of molecular sciences.

[8]  Sudhir Kumar,et al.  Structural dynamics flexibility informs function and evolution at a proteome scale , 2013, Evolutionary applications.

[9]  Heather A Carlson,et al.  Exploring experimental sources of multiple protein conformations in structure-based drug design. , 2007, Journal of the American Chemical Society.

[10]  Modesto Orozco,et al.  A consensus view of protein dynamics , 2007, Proceedings of the National Academy of Sciences.

[11]  Vincent J Hilser,et al.  An Ensemble View of Allostery , 2010, Science.

[12]  Nathalie Reuter,et al.  WEBnm@: a web application for normal mode analyses of proteins , 2005, BMC Bioinformatics.

[13]  H. Rüterjans,et al.  Limits of NMR structure determination using variable target function calculations: ribonuclease T1, a case study. , 1997, Journal of molecular biology.

[14]  Michele Vendruscolo,et al.  Determination of conformationally heterogeneous states of proteins. , 2007, Current opinion in structural biology.

[15]  Andrzej Kolinski,et al.  Simulation of Chaperonin Effect on Protein Folding: A Shift from Nucleation–Condensation to Framework Mechanism , 2011, Journal of the American Chemical Society.

[16]  A. Kolinski.  Protein modeling and structure prediction with a reduced representation. , 2004, Acta biochimica Polonica.

[17]  A. Kolinski,et al.  Characterization of protein-folding pathways by reduced-space modeling , 2007, Proceedings of the National Academy of Sciences.

[18]  Nathaniel Echols,et al.  Accessing protein conformational ensembles using room-temperature X-ray crystallography , 2011, Proceedings of the National Academy of Sciences.

[19]  Modesto Orozco,et al.  Coarse-grained representation of protein flexibility. Foundations, successes, and shortcomings. , 2011, Advances in protein chemistry and structural biology.

[20]  Douglas L. Theobald,et al.  THESEUS: maximum likelihood superpositioning and analysis of macromolecular structures , 2006, Bioinform..

[21]  István Simon,et al.  Bioinformatical Approaches to Unstructured/Disordered Proteins and Their Interactions , 2014 .

[22]  I. Kuntz,et al.  Molecular docking to ensembles of protein structures. , 1997, Journal of molecular biology.

[23]  W. V. van Gunsteren,et al.  Time-averaged nuclear Overhauser effect distance restraints applied to tendamistat. , 1990, Journal of molecular biology.

[24]  Janusz M Bujnicki,et al.  Generalized protein structure prediction based on combination of fold‐recognition with de novo folding and evaluation of models , 2005, Proteins.

[25]  Andrzej Kolinski,et al.  CABS-flex: server for fast simulation of protein structure fluctuations , 2013, Nucleic Acids Res..

[26]  Modesto Orozco,et al.  Consistent View of Protein Fluctuations from All-Atom Molecular Dynamics and Coarse-Grained Dynamics with Knowledge-Based Force-Field. , 2013, Journal of chemical theory and computation.

[27]  Bernard F. Buxton,et al.  The DISOPRED server for the prediction of protein disorder , 2004, Bioinform..

[28]  Xavier Salvatella,et al.  Understanding biomolecular motion, recognition, and allostery by use of conformational ensembles , 2011, European Biophysics Journal.

[29]  Dominik Gront,et al.  Optimization of protein models , 2012 .

[30]  Andrzej Kolinski,et al.  Multiscale Approach to Protein Folding Dynamics , 2011 .

[31]  Sebastian Doniach,et al.  Protein flexibility in solution and in crystals , 1999 .

[32]  Dominik Gront,et al.  BMC Structural Biology BioMed Central , 2007 .

[33]  Jianpeng Ma,et al.  Usefulness and limitations of normal mode analysis in modeling dynamics of biomolecular complexes. , 2005, Structure.

[34]  Michael Nilges,et al.  Structural Biology by NMR: Structure, Dynamics, and Interactions , 2008, PLoS Comput. Biol..

[35]  Erin S. Bolstad,et al.  In pursuit of virtual lead optimization: The role of the receptor structure and ensembles in accurate docking , 2008, Proteins.

[36]  A. Amadei,et al.  Structure from NMR and molecular dynamics: Distance restraining inhibits motion in the essential subspace , 1995, Journal of biomolecular NMR.

[37]  Adam Liwo,et al.  Investigation of protein folding by coarse-grained molecular dynamics with the UNRES force field. , 2010, The journal of physical chemistry. A.

[38]  Modesto Orozco,et al.  MoDEL (Molecular Dynamics Extended Library): a database of atomistic molecular dynamics trajectories. , 2010, Structure.

[39]  Dominik Gront,et al.  From coarse-grained to atomic-level characterization of protein dynamics: transition state for the folding of B domain of protein A. , 2012, The journal of physical chemistry. B.

[40]  Andrzej Kolinski,et al.  CABS-fold: server for the de novo and consensus-based prediction of protein structure , 2013, Nucleic Acids Res..

[41]  Modesto Orozco,et al.  Exploring the suitability of coarse-grained techniques for the representation of protein dynamics. , 2008, Biophysical journal.

[42]  M. DePristo,et al.  Is one solution good enough? , 2006, Nature Structural &Molecular Biology.

[43]  G. Petsko,et al.  Crystalline ribonuclease A loses function below the dynamical transition at 220 K , 1992, Nature.