Insights into Equilibrium Dynamics of Proteins from Comparison of NMR and X-Ray Data with Computational Predictions

Yang, Lee‐Wei; Eyal, Eran; Chennubhotla, Chakra; Jee, Jun-Goo; Gronenborn, Angela M.; Bahar, İvet

doi:10.1016/j.str.2007.04.014

Cited by 127 publications

(155 citation statements)

References 41 publications

Supporting

Mentioning

143

Contrasting

Unclassified

Order By: Relevance

“…66 It is also possible to use a set of experimental structures in different liganded complexes (if they are available) to compute the binding induced dynamics. [67][68][69][70] The recent study of Bakan and Bahar has shown that ENM predicted modes are very well correlated with the principal components of the conformational change for a large set of different liganded experimental structures of a given protein. 71 We have repeated the same analysis for our test protein: PDZ domain.…”

Section: Elastic Network Model and Generating New Conformations Usingmentioning

confidence: 96%

A flexible docking scheme to explore the binding selectivity of PDZ domains

Gerek

Ozkan

2010

Protein Science

View full text Add to dashboard Cite

Modeling of protein binding site flexibility in molecular docking is still a challenging problem due to the large conformational space that needs sampling. Here, we propose a flexible receptor docking scheme: A dihedral restrained replica exchange molecular dynamics (REMD), where we incorporate the normal modes obtained by the Elastic Network Model (ENM) as dihedral restraints to speed up the search towards correct binding site conformations. To our knowledge, this is the first approach that uses ENM modes to bias REMD simulations towards binding induced fluctuations in docking studies. In our docking scheme, we first obtain the deformed structures of the unbound protein as initial conformations by moving along the binding fluctuation mode, and perform REMD using the ENM modes as dihedral restraints. Then, we generate an ensemble of multiple receptor conformations (MRCs) by clustering the lowest replica trajectory. Using ROSETTALIGAND, we dock ligands to the clustered conformations to predict the binding pose and affinity. We apply this method to postsynaptic density-95/Dlg/ZO-1 (PDZ) domains; whose dynamics govern their binding specificity. Our approach produces the lowest energy bound complexes with an average ligand root mean square deviation of 0.36 Å . We further test our method on (i) homologs and (ii) mutant structures of PDZ where mutations alter the binding selectivity. In both cases, our approach succeeds to predict the correct pose and the affinity of binding peptides. Overall, with this approach, we generate an ensemble of MRCs that leads to predict the binding poses and specificities of a protein complex accurately.

show abstract

Section: Elastic Network Model and Generating New Conformations Usingmentioning

confidence: 96%

A flexible docking scheme to explore the binding selectivity of PDZ domains

Gerek

Ozkan

2010

Protein Science

View full text Add to dashboard Cite

show abstract

“…The only information required to implement the method is the knowledge of the native structure obtained from the PDB (26). The GNM has been widely applied because it yields results in agreement with X-ray spectroscopy and NMR experiments (17,27). In order to study diffusion, we transform all springs in the GNM into edges creating a three-dimensional network of nodes.…”

Section: Diffusion On the Protein Foldmentioning

confidence: 99%

Anomalies in the vibrational dynamics of proteins are a consequence of fractal-like structure

Reuveni

Granek

Klafter

2010

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Proteins have been shown to exhibit strange/anomalous dynamics displaying non-Debye density of vibrational states, anomalous spread of vibrational energy, large conformational changes, nonexponential decay of correlations, and nonexponential unfolding times. The anomalous behavior may, in principle, stem from various factors affecting the energy landscape under which a protein vibrates. Investigating the origins of such unconventional dynamics, we focus on the structure-dynamics interplay and introduce a stochastic approach to the vibrational dynamics of proteins. We use diffusion, a method sensitive to the structural features of the protein fold and them alone, in order to probe protein structure. Conducting a large-scale study of diffusion on over 500 Protein Data Bank structures we find it to be anomalous, an indication of a fractal-like structure. Taking advantage of known and newly derived relations between vibrational dynamics and diffusion, we demonstrate the equivalence of our findings to the existence of structurally originated anomalies in the vibrational dynamics of proteins. We conclude that these anomalies are a direct result of the fractal-like structure of proteins. The duality between diffusion and vibrational dynamics allows us to make, on a single-molecule level, experimentally testable predictions. The time dependent vibrational mean square displacement of an amino acid is predicted to be subdiffusive. The thermal variance in the instantaneous distance between amino acids is shown to grow as a power law of the equilibrium distance. Mean first passage time analysis is offered as a practical tool that may aid in the identification of amino acid pairs involved in large conformational changes.protein dynamics | Gaussian network model | anomalous diffusion | intramolecular distance distributions | mean first passage time IntroductionProteins are commonly envisioned vibrating under the influence of a complicated energy landscape (1) held responsible for their intricate dynamics (1-9). Despite its overall complexity the energy landscape is approximately harmonic near its minima, a fact that does not seem to coincide with the rich dynamics mentioned above. Attacking the validity of the harmonic approximation is one way out of this puzzle. One might have suggested that the harmonic approximation is unable to capture the anomalous dynamics displayed by proteins since the latter is dominated by large excursions from the native state structure. The failure of the harmonic approximation then follows from the fact that it does not describe the energy of conformations which considerably deviate from the native state structure. In this paper we argue differently showing that the native state structure of proteins is fractal-like and hence anomalous in its basis. As a result one needs not go beyond the harmonic approximation in order to observe anomalous dynamics since anomalous structure leads to it even in the presence of the simplest interactions. Interestingly, when the structure is fractal-like, large con...

show abstract

“…We then explore the use of these two reference structures to support the evaluation of the significance of the few apparent differences between the experimental NMR and crystal structures. While systematic comparisons of crystal structures and NMR structures have been carried out for many years (see, for example, Billeter et al, 1989;Braun et al, 1989Braun et al, , 1992Hyberts et al, 1992;Yang et al, 2007), owing to the advancement of the two methodologies and the automated methods that can reduce human error or bias, we can now focus on more subtle differences between the NMR and crystal structures that might in some instances also relate to the biological function. The identification of such locally variable sites is guided by a search for sequence locations with high B values in the crystal structure or/and high variation within the bundle of 20 NMR conformers.…”

Section: Strategy For Structure Comparisonsmentioning

confidence: 99%

NMR structure of the protein NP_247299.1: comparison with the crystal structure

et al. 2010

View full text Add to dashboard Cite

The NMR structure of the protein NP_247299.1 in solution at 313 K has been determined and is compared with the X-ray crystal structure, which was also solved in the Joint Center for Structural Genomics (JCSG) at 100 K and at 1.7 Å resolution. Both structures were obtained using the current largely automated crystallographic and solution NMR methods used by the JCSG. This paper assesses the accuracy and precision of the results from these recently established automated approaches, aiming for quantitative statements about the location of structure variations that may arise from either one of the methods used or from the different environments in solution and in the crystal. To evaluate the possible impact of the different software used for the crystallographic and the NMR structure determinations and analysis, the concept is introduced of reference structures, which are computed using the NMR software with input of upper-limit distance constraints derived from the molecular models representing the results of the two structure determinations. The use of this new approach is explored to quantify global differences that arise from the different methods of structure determination and analysis versus those that represent interesting local variations or dynamics. The near-identity of the protein core in the NMR and crystal structures thus provided a basis for the identification of complementary information from the two different methods. It was thus observed that locally increased crystallographic B values correlate with dynamic structural polymorphisms in solution, including that the solution state of the protein involves a slow dynamic equilibrium on a time scale of milliseconds or slower between two ensembles of rapidly interchanging conformers that contain, respectively, the cis or trans form of the C-terminal proline and represent about 25 and 75% of the total protein.

show abstract

Insights into Equilibrium Dynamics of Proteins from Comparison of NMR and X-Ray Data with Computational Predictions

Cited by 127 publications

References 41 publications

A flexible docking scheme to explore the binding selectivity of PDZ domains

A flexible docking scheme to explore the binding selectivity of PDZ domains

Anomalies in the vibrational dynamics of proteins are a consequence of fractal-like structure

NMR structure of the protein NP_247299.1: comparison with the crystal structure

Contact Info

Product

Resources

About