Browse
Submit Data
Databases
API
Help

Dataset Information

23 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Insights into protein flexibility: The relationship between normal modes and conformational change upon protein-protein docking.

ABSTRACT: Understanding protein interactions has broad implications for the mechanism of recognition, protein design, and assigning putative functions to uncharacterized proteins. Studying protein flexibility is a key component in the challenge of describing protein interactions. In this work, we characterize the observed conformational change for a set of 20 proteins that undergo large conformational change upon association (>2 A Calpha RMSD) and ask what features of the motion are successfully reproduced by the normal modes of the system. We demonstrate that normal modes can be used to identify mobile regions and, in some proteins, to reproduce the direction of conformational change. In 35% of the proteins studied, a single low-frequency normal mode was found that describes well the direction of the observed conformational change. Finally, we find that for a set of 134 proteins from a docking benchmark that the characteristic frequencies of normal modes can be used to predict reliably the extent of observed conformational change. We discuss the implications of the results for the mechanics of protein recognition.

SUBMITTER: Dobbins SE

PROVIDER: S-EPMC2475499 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Can conformational change be described by only a few normal modes?

Project description:We suggest a simple method to assess how many normal modes are needed to map a conformational change. By projecting the conformational change onto a subspace of the normal-mode vectors and using root mean square deviation as a test of accuracy, we find that the first 20 modes only contribute 50% or less of the total conformational change in four test cases (myosin, calmodulin, NtrC, and hemoglobin). In some allosteric systems, like the molecular switch NtrC, the conformational change is localized to a limited number of residues. We find that many more modes are necessary to accurately map this collective displacement. In addition, the normal-mode "spectra" can provide useful information about the details of the conformational change, especially when comparing structures with different bound ligands, in this case, calmodulin. Indeed, this approach presents normal-mode analysis as a useful basis in which to capture the mechanism of conformational change, and shows that the number of normal modes needed to capture the essential collective motions of atoms should be chosen according to the required accuracy.

| S-EPMC1367309 | biostudies-literature

SwarmDock and the use of normal modes in protein-protein docking.

Project description:Here is presented an investigation of the use of normal modes in protein-protein docking, both in theory and in practice. Upper limits of the ability of normal modes to capture the unbound to bound conformational change are calculated on a large test set, with particular focus on the binding interface, the subset of residues from which the binding energy is calculated. Further, the SwarmDock algorithm is presented, to demonstrate that the modelling of conformational change as a linear combination of normal modes is an effective method of modelling flexibility in protein-protein docking.

| S-EPMC2996808 | biostudies-literature

Flexibility, conformational diversity and two dimerization modes in complexes of ribosomal protein L12.

Project description:Protein L12, the only multicopy component of the ribosome, is presumed to be involved in the binding of translation factors, stimulating factor-dependent GTP hydrolysis. Crystal structures of L12 from Thermotogamaritima have been solved in two space groups by the multiple anomalous dispersion method and refined at 2.4 and 2.0 A resolution. In both crystal forms, an asymmetric unit comprises two full-length L12 molecules and two N-terminal L12 fragments that are associated in a specific, hetero-tetrameric complex with one non-crystallographic 2-fold axis. The two full-length proteins form a tight, symmetric, parallel dimer, mainly through their N-terminal domains. Each monomer of this central dimer additionally associates in a different way with an N-terminal L12 fragment. Both dimerization modes are unlike models proposed previously and suggest that similar complexes may occur in vivo and in situ. The structures also display different L12 monomer conformations, in accord with the suggested dynamic role of the protein in the ribosomal translocation process. The structures have been submitted to the Protein Databank (http://www.rcsb.org/pdb) under accession numbers 1DD3 and 1DD4.

| S-EPMC305552 | biostudies-literature

Instantaneous normal modes as an unforced reaction coordinate for protein conformational transitions.

Project description:We present a novel sampling approach to explore large protein conformational transitions by determining unique substates from instantaneous normal modes calculated from an elastic network model, and applied to a progression of atomistic molecular dynamics snapshots. This unbiased sampling scheme allows us to direct the path sampling between the conformational end states over simulation timescales that are greatly reduced relative to the known experimental timescales. We use adenylate kinase as a test system to show that instantaneous normal modes can be used to identify substates that drive the structural fluctuations of adenylate kinase from its closed to open conformations, in which we observe 16 complete transitions in 4 mus of simulation time, reducing the timescale over conventional simulation timescales by two orders of magnitude. Analysis shows that the unbiased determination of substates is consistent with known pathways determined experimentally.

| S-EPMC2872262 | biostudies-literature

Normal-modes-based prediction of protein conformational changes guided by distance constraints.

Project description:Based on the elastic network model, we develop a novel method that predicts the conformational change of a protein complex given its initial-state crystal structure together with a small set of pairwise distance constraints for the end state. The predicted conformational change, which is a linear combination of multiple low-frequency normal modes that are solved from the elastic network model, is computed as a response displacement induced by a perturbation to the system Hamiltonian that incorporates the given distance constraints. For a list of test cases, we find that the computed response displacement overlaps significantly with the measured conformational changes, when only a handful of pairwise constraints are used (</=10). The performance of this method is also shown to be robust against different choices of pairwise distance constraints and errors in their values. This method, if supplied with the experimentally derived distance constraints (for example, from NMR or other spectroscopic measurements), can be applied to the analysis of protein conformational changes toward transient states.

| S-EPMC1305462 | biostudies-literature

Conformational change in the activation of lipase: an analysis in terms of low-frequency normal modes.

Project description:The interfacial activation of Rhizomucor miehei lipase (RmL) involves the motion of an alpha-helical region (residues 82-96) which acts as a "lid" over the active site of the enzyme, undergoing a displacement from a "closed" to an "open" conformation upon binding of substrate. Normal mode analyses performed in both low and high dielectric media reveal that low-frequency vibrational modes contribute significantly to the conformational transition between the closed and open conformations. In these modes, the lid displacement is coupled to local motions of active site loops as well as global breathing motions. Atomic fluctuations of the first hinge of the lid (residues 83-84) are substantially larger in the low dielectric medium than in the high dielectric medium. Our results also suggest that electrostatic interactions of Arg86 play an important role in terms of both the intrinsic stability of the lid and its displacement, through enhancement of hinge mobility in a high dielectric medium. Additional calculations demonstrate that the observed patterns of atomic fluctuations are an intrinsic feature of the protein structure and not dependent on the nature of specific energy minima.

| S-EPMC2144042 | biostudies-other

Modeling protein conformational changes by iterative fitting of distance constraints using reoriented normal modes.

Project description:Recently we have developed a normal-modes-based algorithm that predicts the direction of protein conformational changes given the initial state crystal structure together with a small number of pairwise distance constraints for the end state. Here we significantly extend this method to accurately model both the direction and amplitude of protein conformational changes. The new protocol implements a multisteps search in the conformational space that is driven by iteratively minimizing the error of fitting the given distance constraints and simultaneously enforcing the restraint of low elastic energy. At each step, an incremental structural displacement is computed as a linear combination of the lowest 10 normal modes derived from an elastic network model, whose eigenvectors are reorientated to correct for the distortions caused by the structural displacements in the previous steps. We test this method on a list of 16 pairs of protein structures for which relatively large conformational changes are observed (root mean square deviation >3 angstroms), using up to 10 pairwise distance constraints selected by a fluctuation analysis of the initial state structures. This method has achieved a near-optimal performance in almost all cases, and in many cases the final structural models lie within root mean square deviation of 1 approximately 2 angstroms from the native end state structures.

| S-EPMC1471861 | biostudies-literature

Optimized torsion-angle normal modes reproduce conformational changes more accurately than cartesian modes.

Project description:We present what to our knowledge is a new method of optimized torsion-angle normal-mode analysis, in which the normal modes move along curved paths in Cartesian space. We show that optimized torsion-angle normal modes reproduce protein conformational changes more accurately than Cartesian normal modes. We also show that orthogonalizing the displacement vectors from torsion-angle normal-mode analysis and projecting them as straight lines in Cartesian space does not lead to better performance than Cartesian normal modes. Clearly, protein motion is more naturally described by curved paths in Cartesian space.

| S-EPMC3244061 | biostudies-literature

Incorporation of protein flexibility and conformational energy penalties in docking screens to improve ligand discovery.

Project description:Proteins fluctuate between alternative conformations, which presents a challenge for ligand discovery because such flexibility is difficult to treat computationally owing to problems with conformational sampling and energy weighting. Here we describe a flexible docking method that samples and weights protein conformations using experimentally derived conformations as a guide. The crystallographically refined occupancies of these conformations, which are observable in an apo receptor structure, define energy penalties for docking. In a large prospective library screen, we identified new ligands that target specific receptor conformations of a cavity in cytochrome c peroxidase, and we confirm both ligand pose and associated receptor conformation predictions by crystallography. The inclusion of receptor flexibility led to ligands with new chemotypes and physical properties. By exploiting experimental measures of loop and side-chain flexibility, this method can be extended to the discovery of new ligands for hundreds of targets in the Protein Data Bank for which similar experimental information is available.

| S-EPMC4144196 | biostudies-literature

Mechanism of signal propagation upon retinal isomerization: insights from molecular dynamics simulations of rhodopsin restrained by normal modes.

Project description:As one of the best studied members of the pharmaceutically relevant family of G-protein-coupled receptors, rhodopsin serves as a prototype for understanding the mechanism of G-protein-coupled receptor activation. Here, we aim at exploring functionally relevant conformational changes and signal transmission mechanisms involved in its photoactivation brought about through a cis-trans photoisomerization of retinal. For this exploration, we propose a molecular dynamics simulation protocol that utilizes normal modes derived from the anisotropic network model for proteins. Deformations along multiple low-frequency modes of motion are used to efficiently sample collective conformational changes in the presence of explicit membrane and water environment, consistent with interresidue interactions. We identify two highly stable regions in rhodopsin, one clustered near the chromophore, the other near the cytoplasmic ends of transmembrane helices H1, H2, and H7. Due to redistribution of interactions in the neighborhood of retinal upon stabilization of the trans form, local structural rearrangements in the adjoining H3-H6 residues are efficiently propagated to the cytoplasmic end of these particular helices. In the structures obtained by our simulations, all-trans retinal interacts with Cys(167) on H4 and Phe(203) on H5, which were not accessible in the dark state, and exhibits stronger interactions with H5, while some of the contacts made (in the cis form) with H6 are lost.

| S-EPMC2440475 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data