Close Correspondence between the Motions from Principal Component Analysis of Multiple HIV-1 Protease Structures and Elastic Network Modes

Yang, Lei; Song, Guang; Carriquiry, Alicia L.; Jernigan, Robert L.

doi:10.1016/j.str.2007.12.011

Cited by 165 publications

(211 citation statements)

References 38 publications

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“…5c). The lowest and second lowest frequency modes calculated by normal mode analysis 42 corresponded to similar motions in the molecule than the first and second PC, as typically found with other biomolecules 43 .…”

Section: Saxs Experimentssupporting

confidence: 68%

Structure of the full-length HCV IRES in solution

et al. 2013

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The 5 0 -untranslated region of the hepatitis C virus genome contains an internal ribosome entry site (IRES) that initiates cap-independent translation of the viral RNA. Until now, the structural characterization of the entire (IRES) remained limited to cryo-electron microscopy reconstructions of the (IRES) bound to different cellular partners. Here we report an atomic model of free full-length hepatitis C virus (IRES) refined by selection against small-angle X-ray scattering data that incorporates the known structures of different fragments. We found that an ensemble of conformers reproduces small-angle X-ray scattering data better than a single structure suggesting in combination with molecular dynamics simulations that the hepatitis C virus (IRES) is an articulated molecule made of rigid parts that move relative to each other. Principal component analysis on an ensemble of physically accessible conformers of hepatitis C virus (IRES) revealed dominant collective motions in the molecule, which may underlie the conformational changes occurring in the (IRES) molecule upon formation of the initiation complex.

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Section: Saxs Experimentssupporting

confidence: 68%

Structure of the full-length HCV IRES in solution

et al. 2013

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“…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: 95%

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

Gerek

Ozkan

2010

Protein Science

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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.

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“…Overlap between ANM modes and PCs is evaluated using the correlation cosine between the eigenvectors, 51,52 …”

Section: Overlap Between Anm Modes and Pcsmentioning

confidence: 99%

Global motions exhibited by proteins in micro- to milliseconds simulations concur with anisotropic network model predictions

Gür

Zomot

Bahar

2013

The Journal of Chemical Physics

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The Anton supercomputing technology recently developed for efficient molecular dynamics simulations permits us to examine micro-to milli-second events at full atomic resolution for proteins in explicit water and lipid bilayer. It also permits us to investigate to what extent the collective motions predicted by network models (that have found broad use in molecular biophysics) agree with those exhibited by full-atomic long simulations. The present study focuses on Anton trajectories generated for two systems: the bovine pancreatic trypsin inhibitor, and an archaeal aspartate transporter, GltPh. The former, a thoroughly studied system, helps benchmark the method of comparative analysis, and the latter provides new insights into the mechanism of function of glutamate transporters. The principal modes of motion derived from both simulations closely overlap with those predicted for each system by the anisotropic network model (ANM). Notably, the ANM modes define the collective mechanisms, or the pathways on conformational energy landscape, that underlie the passage between the crystal structure and substates visited in simulations. In particular, the lowest frequency ANM modes facilitate the conversion between the most probable substates, lending support to the view that easy access to functional substates is a robust determinant of evolutionarily selected native contact topology.

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Close Correspondence between the Motions from Principal Component Analysis of Multiple HIV-1 Protease Structures and Elastic Network Modes

Cited by 165 publications

References 38 publications

Structure of the full-length HCV IRES in solution

Structure of the full-length HCV IRES in solution

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

Global motions exhibited by proteins in micro- to milliseconds simulations concur with anisotropic network model predictions

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