CABS-flex predictions of protein flexibility compared with NMR ensembles (original) (raw)
Related papers
2017
Proteins are molecular machines requiring flexibility to function. Crystallographic B-factors and Molecular Dynamics (MD) simulations both provide insights into protein flexibility on an atomic scale. Nuclear Magnetic Resonance (NMR) lacks a universally accepted analog of the B-factor, however, a lack of convergence in atomic coordinates in an NMR-based structure calculation also suggests atomic mobility. This paper describes a pattern in the coordinate uncertainties of backbone heavy atoms in NMR-derived structural “ensembles” first noted in the development of FindCore2 (previously called Expanded FindCore: DA Snyder, J Grullon, YJ Huang, R Tejero, GT Montelione, Proteins: Structure, Function, and Bioinformatics 82 (S2), 219–230) and demonstrates that this pattern exists in coordinate variances across MD trajectories but not in crystallographic B-factors. This either suggests that MD trajectories and NMR “ensembles” capture motional behavior of peptide bond units not captured by B-...
CoNSEnsX: an ensemble view of protein structures and NMR-derived experimental data
BMC Structural Biology, 2010
Background: In conjunction with the recognition of the functional role of internal dynamics of proteins at various timescales, there is an emerging use of dynamic structural ensembles instead of individual conformers. These ensembles are usually substantially more diverse than conventional NMR ensembles and eliminate the expectation that a single conformer should fulfill all NMR parameters originating from 10 16 -10 17 molecules in the sample tube. Thus, the accuracy of dynamic conformational ensembles should be evaluated differently to that of single conformers. Results: We constructed the web application CoNSEnsX (Consistency of NMR-derived Structural Ensembles with eXperimental data) allowing fast, simple and convenient assessment of the correspondence of the ensemble as a whole with diverse independent NMR parameters available. We have chosen different ensembles of three proteins, human ubiquitin, a small protease inhibitor and a disordered subunit of cGMP phosphodiesterase 5/6 for detailed evaluation and demonstration of the capabilities of the CoNSEnsX approach. Conclusions: Our results present a new conceptual method for the evaluation of dynamic conformational ensembles resulting from NMR structure determination. The designed CoNSEnsX approach gives a complete evaluation of these ensembles and is freely available as a web service at
Synergistic use of NMR and MD simulations to study the structural heterogeneity of proteins
Wiley Interdisciplinary Reviews: Computational Molecular Science, 2012
ABSTRACT Nuclear magnetic resonance spectroscopy (NMR) and molecular dynamics (MD) simulations are powerful techniques for the structural characterization of macromolecules. NMR is unique in its ability to provide experimental information at atomic level on the structure as well as on the amplitude and rate of structural fluctuations. MD provides physically sound models and potential mechanisms that connect conformations in time. Nevertheless, none of these techniques allow yet obtaining experimentally validated movies of protein motions at atomic resolution. Instead, it is their complementarity and synergy which offer a unique opportunity toward this end. Here, we overview recent examples that illustrate how much these two techniques benefit from each other, both passively and actively, for the characterization of the structural heterogeneity in proteins. © 2012 John Wiley & Sons, Ltd.
Using NMR Chemical Shifts as Structural Restraints in Molecular Dynamics Simulations of Proteins
Structure, 2010
We introduce a procedure to determine the structures of proteins by incorporating NMR chemical shifts as structural restraints in molecular dynamics simulations. In this approach, the chemical shifts are expressed as differentiable functions of the atomic coordinates and used to compute forces to generate trajectories that lead to the reduction of the differences between experimental and calculated chemical shifts. We show that this strategy enables the folding of a set of proteins with representative topologies starting from partially denatured initial conformations without the use of additional experimental information. This method also enables the straightforward combination of chemical shifts with other standard NMR restraints, including those derived from NOE, J-coupling, and residual dipolar coupling measurements. We illustrate this aspect by calculating the structure of a transiently populated excited state conformation from chemical shift and residual dipolar coupling data measured by relaxation dispersion NMR experiments. Structure Molecular Dynamics with Chemical Shift Restraints 924 Structure 18, 923-933, August 11,
Deciphering Protein Dynamics from NMR Data Using Explicit Structure Sampling and Selection
Biophysical Journal, 2007
Perhaps one of the most prominent realizations of recent years is the critical role that protein dynamics plays in many facets of cellular function. While characterization of protein dynamics is fundamental to our understanding of protein function, the ability to explicitly detect an ensemble of protein conformations from dynamics data is a paramount challenge in structural biology. Here, we report a new computational method, Sample and Select, for determining the ensemble of protein conformations consistent with NMR dynamics data. This method can be generalized and extended to different sources of dynamics data, enabling broad applicability in deciphering protein dynamics at different timescales. The structural ensemble derived from Sample and Select will provide structural and dynamic information that should aid us in understanding and manipulating protein function.
CABS-flex: server for fast simulation of protein structure fluctuations
Nucleic Acids Research, 2013
The CABS-flex server (http://biocomp.chem.uw.edu.pl/CABSflex) implements CABS-model-based protocol for the fast simulations of near-native dynamics of globular proteins. In this application, the CABS model was shown to be a computationally efficient alternative to all-atom molecular dynamics--a classical simulation approach. The simulation method has been validated on a large set of molecular dynamics simulation data. Using a single input (user-provided file in PDB format), the CABS-flex server outputs an ensemble of protein models (in all-atom PDB format) reflecting the flexibility of the input structure, together with the accompanying analysis (residue mean-square-fluctuation profile and others). The ensemble of predicted models can be used in structure-based studies of protein functions and interactions.
Given the demonstrated utility of coarse-grained modeling and simulations approaches in studying protein structure and dynamics, developing methods that allow experimental observables to be directly recovered from coarse-grained models is of great importance. In this work, we develop one such method that enables protein backbone chemical shifts (1HN, 1Hα, 13Cα, 13C, 13Cβ, and 15N) to be predicted from Cα coordinates. We show that our Cα-based method, LARMORCα, predicts backbone chemical shifts with comparable accuracy to some all-atom approaches. More importantly, we demonstrate that LARMORCα predicted chemical shifts are able to resolve native structure from decoy pools that contain both native and non-native models, and so it is sensitive to protein structure. As an application, we use LARMORCα to characterize the transient state of the fast-folding protein gpW using recently published NMR relaxation dispersion derived backbone chemical shifts. The model we obtain is consistent with the previously proposed model based on independent analysis of the chemical shift dispersion pattern of the transient state. We anticipate that LARMORCα will find utility as a tool that enables important protein conformational substates to be identified by “parsing” trajectories and ensembles generated using coarse-grained modeling and simulations.
Local Fluctuations and Conformational Transitions in Proteins
Journal of Chemical Theory and Computation, 2012
The intrinsic plasticity of protein residues, along with the occurrence of transitions between distinct residue conformations, plays a pivotal role in a variety of molecular recognition events in the cell. Analysis aimed at identifying both of these features has been limited so far to protein-complex structures. We present a computationally efficient tool (T-pad), which quantitatively analyzes protein residues' flexibility and detects backbone conformational transitions. T-pad is based on directional statistics of NMR structural ensembles or molecular dynamics trajectories. T-pad is here applied to human ubiquitin (hU), a paradigmatic cellular interactor. The calculated plasticity is compared to hU's Debye−Waller factors from the literature as well as those from experimental work carried out for this paper. T-pad is able to identify most of the key residues involved in hU's molecular recognition, also in the absence of its cellular partners. Indeed, T-pad identified as many as 90% of ubiquitin residues interacting with their cognate proteins. Hence, T-pad might be a useful tool for the investigation of interactions between proteins and their cellular partners at the genome-wide level.
Equilibrium simulations of proteins using molecular fragment replacement and NMR chemical shifts
Proceedings of the National Academy of Sciences of the United States of America, 2014
Methods of protein structure determination based on NMR chemical shifts are becoming increasingly common. The most widely used approaches adopt the molecular fragment replacement strategy, in which structural fragments are repeatedly reassembled into different complete conformations in molecular simulations. Although these approaches are effective in generating individual structures consistent with the chemical shift data, they do not enable the sampling of the conformational space of proteins with correct statistical weights. Here, we present a method of molecular fragment replacement that makes it possible to perform equilibrium simulations of proteins, and hence to determine their free energy landscapes. This strategy is based on the encoding of the chemical shift information in a probabilistic model in Markov chain Monte Carlo simulations. First, we demonstrate that with this approach it is possible to fold proteins to their native states starting from extended structures. Secon...