Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Bray JK

PROVIDER: S-EPMC3244061 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Bray Jenelle K JK Weiss Dahlia R DR Levitt Michael M

Biophysical journal 20111220 12

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 ...[more]

PMID: 22208195

Similar Datasets

Project description:Cyclin-dependent kinases (CDKs) and their associated regulatory cyclins are central for timely regulation of cell-cycle progression. They constitute attractive pharmacological targets for development of anticancer therapeutics, since they are frequently deregulated in human cancers and contribute to sustained, uncontrolled tumor proliferation. Characterization of their structural/dynamic features is essential to gain in-depth insight into structure-activity relationships. In addition, the identification of druggable pockets or key intermediate conformations yields potential targets for the development of novel classes of inhibitors. Structural studies of CDK2/cyclin A have provided a wealth of information concerning monomeric/heterodimeric forms of this kinase. There is, however, much less structural information for other CDK/cyclin complexes, including CDK4/cyclin D1, which displays an alternative (open) position of the cyclin partner relative to CDK, contrasting with the closed CDK2/cyclin A conformation. In this study, we carried out normal-mode analysis and enhanced sampling simulations with our recently developed method, molecular dynamics with excited normal modes, to understand the conformational equilibrium on these complexes. Interestingly, the lowest-frequency normal mode computed for each complex described the transition between the open and closed conformations. Exploration of these motions with an explicit-solvent representation using molecular dynamics with excited normal modes confirmed that the closed conformation is the most stable for the CDK2/cyclin A complex, in agreement with their experimentally available structures. On the other hand, we clearly show that an open↔closed equilibrium may exist in CDK4/cyclin D1, with closed conformations resembling that captured for CDK2/cyclin A. Such conformational preferences may result from the distinct distributions of frustrated contacts in each complex. Using the same approach, the putative roles of the Thr(160) phosphoryl group and the T-loop conformation were investigated. These results provide a dynamic view of CDKs revealing intermediate conformations not yet characterized for CDK members other than CDK2, which will be useful for the design of inhibitors targeting critical conformational transitions.

Project description:PurposeTo develop a robust and efficient reconstruction framework that provides high-quality motion-compensated respiratory-resolved images from free-breathing 3D whole-heart Cartesian coronary magnetic resonance angiography (CMRA) acquisitions.MethodsRecently, XD-GRASP (eXtra-Dimensional Golden-angle RAdial Sparse Parallel MRI) was proposed to achieve 100% scan efficiency and provide respiratory-resolved 3D radial CMRA images by exploiting sparsity in the respiratory dimension. Here, a reconstruction framework for Cartesian CMRA imaging is proposed, which provides respiratory-resolved motion-compensated images by incorporating 2D beat-to-beat translational motion information to increase sparsity in the respiratory dimension. The motion information is extracted from interleaved image navigators and is also used to compensate for 2D translational motion within each respiratory phase. The proposed Optimized Respiratory-resolved Cartesian Coronary MR Angiography (XD-ORCCA) method was tested on 10 healthy subjects and 2 patients with cardiovascular disease, and compared against XD-GRASP.ResultsThe proposed XD-ORCCA provides high-quality respiratory-resolved images, allowing clear visualization of the right and left coronary arteries, even for irregular breathing patterns. Compared with XD-GRASP, the proposed method improves the visibility and sharpness of both coronaries. Significant differences (p < .05) in visible vessel length and proximal vessel sharpness were found between the 2 methods. The XD-GRASP method provides good-quality images in the absence of intraphase motion. However, motion blurring is observed in XD-GRASP images for respiratory phases with larger motion amplitudes and subjects with irregular breathing patterns.ConclusionA robust respiratory-resolved motion-compensated framework for Cartesian CMRA has been proposed and tested in healthy subjects and patients. The proposed XD-ORCCA provides high-quality images for all respiratory phases, independently of the regularity of the breathing pattern.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets