scholarly journals Versatility of Approximating Single-Particle Electron Microscopy Density Maps Using Pseudoatoms and Approximation-Accuracy Control

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Slavica Jonić ◽  
Carlos Oscar S. Sorzano
Keyword(s):  
Electron Microscopy ◽  
Normal Mode ◽  
Conformational Changes ◽  
Normal Mode Analysis ◽  
Approximation Error ◽  
Mode Analysis ◽  
Accuracy Control ◽  
Approximation Accuracy ◽  
Gaussian Functions ◽  
Density Maps

Three-dimensional Gaussian functions have been shown useful in representing electron microscopy (EM) density maps for studying macromolecular structure and dynamics. Methods that require setting a desired number of Gaussian functions or a maximum number of iterations may result in suboptimal representations of the structure. An alternative is to set a desired error of approximation of the given EM map and then optimize the number of Gaussian functions to achieve this approximation error. In this article, we review different applications of such an approach that uses spherical Gaussian functions of fixed standard deviation, referred to as pseudoatoms. Some of these applications use EM-map normal mode analysis (NMA) with elastic network model (ENM) (applications such as predicting conformational changes of macromolecular complexes or exploring actual conformational changes by normal-mode-based analysis of experimental data) while some other do not use NMA (denoising of EM density maps). In applications based on NMA and ENM, the advantage of using pseudoatoms in EM-map coarse-grain models is that the ENM springs are easily assigned among neighboring grains thanks to their spherical shape and uniformed size. EM-map denoising based on the map coarse-graining was so far only shown using pseudoatoms as grains.

scholarly journals A force field for virtual atom molecular mechanics of proteins

2009 ◽  
Vol 106 (37) ◽  
pp. 15667-15672 ◽  
Author(s):  
Anil Korkut ◽  
Wayne A. Hendrickson
Keyword(s):  
Force Field ◽  
Molecular Mechanics ◽  
Normal Mode ◽  
Conformational Changes ◽  
Normal Mode Analysis ◽  
Coarse Grained ◽  
Mode Analysis ◽  
Biological Macromolecules ◽  
Molecular Mechanics Calculations ◽  
Low Degrees

Activities of many biological macromolecules involve large conformational transitions for which crystallography can specify atomic details of alternative end states, but the course of transitions is often beyond the reach of computations based on full-atomic potential functions. We have developed a coarse-grained force field for molecular mechanics calculations based on the virtual interactions of Cα atoms in protein molecules. This force field is parameterized based on the statistical distribution of the energy terms extracted from crystallographic data, and it is formulated to capture features dependent on secondary structure and on residue-specific contact information. The resulting force field is applied to energy minimization and normal mode analysis of several proteins. We find robust convergence in minimizations to low energies and energy gradients with low degrees of structural distortion, and atomic fluctuations calculated from the normal mode analyses correlate well with the experimental B-factors obtained from high-resolution crystal structures. These findings suggest that the virtual atom force field is a suitable tool for various molecular mechanics applications on large macromolecular systems undergoing large conformational changes.

scholarly journals Protein conformational transitions explored by a morphing approach based on normal mode analysis in internal coordinates

PLoS ONE ◽  
2021 ◽  
Vol 16 (11) ◽  
pp. e0258818
Author(s):  
Byung Ho Lee ◽  
Soon Woo Park ◽  
Soojin Jo ◽  
Moon Ki Kim
Keyword(s):  
Normal Mode ◽  
Conformational Changes ◽  
Degrees Of Freedom ◽  
Large Scale ◽  
Conformational Transition ◽  
Normal Mode Analysis ◽  
Mode Analysis ◽  
Theoretical Approaches ◽  
Internal Coordinates ◽  
Transition Pathways

Large-scale conformational changes are essential for proteins to function properly. Given that these transition events rarely occur, however, it is challenging to comprehend their underlying mechanisms through experimental and theoretical approaches. In this study, we propose a new computational methodology called internal coordinate normal mode-guided elastic network interpolation (ICONGENI) to predict conformational transition pathways in proteins. Its basic approach is to sample intermediate conformations by interpolating the interatomic distance between two end-point conformations with the degrees of freedom constrained by the low-frequency dynamics afforded by normal mode analysis in internal coordinates. For validation of ICONGENI, it is applied to proteins that undergo open-closed transitions, and the simulation results (i.e., simulated transition pathways) are compared with those of another technique, to demonstrate that ICONGENI can explore highly reliable pathways in terms of thermal and chemical stability. Furthermore, we generate an ensemble of transition pathways through ICONGENI and investigate the possibility of using this method to reveal the transition mechanisms even when there are unknown metastable states on rough energy landscapes.

scholarly journals Structural Insights into the Allosteric site of Arabidopsis NADP-Malic Enzyme 2: Role of the Second Sphere Residues in the Regulatory Signal Transmission

2021 ◽  
Author(s):  
Mariel Claudia Gerrard Wheeler ◽  
Cintia Lucía Arias ◽  
Juliana Juliana da Fonseca Rezende e Mello ◽  
Nuria Cirauqui Diaz ◽  
Carlos Rangel Rodrigues ◽  
...  
Keyword(s):  
Normal Mode ◽  
Conformational Changes ◽  
Active Site ◽  
Normal Mode Analysis ◽  
Signal Transmission ◽  
Allosteric Regulation ◽  
3D Structure ◽  
Mode Analysis ◽  
Allosteric Site ◽  
Structural Determinants

Abstract Structure-function studies contribute to deciphering how small modifications in the primary structure could introduce desirable characteristics into enzymes without affecting its overall functioning. Malic enzymes (ME) are ubiquitous and responsible for a wide variety of functions. The availability of a high number of ME crystal structures from different species facilitates comparisons between sequence and structure. Specifically, the structural determinants necessary for fumarate allosteric regulation of ME has been of particular interest. NADP-ME2 from Arabidopsis thaliana exhibits a distinctive and complex regulation by fumarate, acting as an activator or an inhibitor according to substrate and effector concentrations. However, the 3D structure for this enzyme is not yet reported. In this work, we characterized the NADP-ME2 allosteric site by structural modeling, molecular docking, normal mode analysis and mutagenesis. The regulatory site model and its docking analysis suggested that other C4 acids including malate, NADP-ME2 substrate, could also fit into fumarate’s pocket. Besides, a non-conserved cluster of hydrophobic residues in the second sphere of the allosteric site was identified. The substitution of one of those residues, L62, by a less flexible residue as tryptophan, resulted in a complete loss of fumarate activation and a reduction of substrate affinities for the active site. In addition, normal mode analysis indicated that conformational changes leading to the activation could originate in the region surrounding L62, extending through the allosteric site till the active site. Finally, the results in this work contribute to the understanding of structural determinants necessary for allosteric regulation providing new insights for enzyme optimization.

scholarly journals Macromolecular Dynamics by Hybrid Electron Microscopy Normal Mode Analysis

2014 ◽  
Vol 20 (S3) ◽  
pp. 1218-1219
Author(s):  
Qiyu Jin ◽  
S. Sorzano Carlos Oscar ◽  
Jose Miguel de la Rosa-Trevín ◽  
Florence Tama ◽  
Slavica Jonić
Keyword(s):  
Electron Microscopy ◽  
Normal Mode ◽  
Normal Mode Analysis ◽  
Mode Analysis ◽  
Macromolecular Dynamics

scholarly journals Unveiling functional motions based on point mutations in biased signaling systems: A normal mode study on Nerve Growth Factor bound to TrkA

2019 ◽  
Author(s):  
Pedro Túlio De Resende Lara ◽  
David Perahia ◽  
Ana Lígia Scott ◽  
Antonio Sergio Kimus Braz
Keyword(s):  
Normal Mode ◽  
Conformational Changes ◽  
Structural Changes ◽  
Normal Mode Analysis ◽  
Methodological Approach ◽  
Point Mutations ◽  
Interaction Network ◽  
Mode Analysis ◽  
Biased Signaling ◽  
Trka Receptors

Many receptors elicit signal transduction by activating multiple intracellular pathways. This transduction may be triggered by a nonspecific ligand, which simultaneously activates all receptor’s signaling paths. In addition, the binding of a biased ligand preferentially elicits one path over another, in a process called biased signaling. Identifying the functional motions related to each one of these distinct pathways have direct impact in the development of new efficient and specific drugs. Here we show how to detect functional motions considering the case of the NGF/TrkA-Ig2 complex. TrkA receptors activation mediated by NGF depends on specific structural motions that trigger neuronal growth, development and survival in nervous system. R221W mutation in the ngf gene impairs the nociceptive signaling. Here we show the wide spread structural effects of this mutation in the NGF/TrkA-Ig2 complex, leading to the deletion of collective motions important to TrkA activation of nociceptive signaling. Our results suggest that subtle changes in the interaction network within neurotrophic factors due to the point mutation are sufficient to inhibit necessary conformational changes for TrkA receptors activation. The methodological approach presented in this article based conjunctively on normal mode analysis and the experimentally observed functional alterations due to point mutations provides an essential tool for unveiling the structural changes and motions related to the disease, that in turn could be important for a drug design study.

scholarly journals HEMNMA-3D: Cryo Electron Tomography Method Based on Normal Mode Analysis to Study Continuous Conformational Variability of Macromolecular Complexes

2021 ◽  
Vol 8 ◽  
Author(s):  
Mohamad Harastani ◽  
Mikhail Eltsov ◽  
Amélie Leforestier ◽  
Slavica Jonic
Keyword(s):  
Data Analysis ◽  
Rigid Body ◽  
Normal Mode ◽  
Conformational Changes ◽  
Electron Tomography ◽  
Normal Mode Analysis ◽  
Mode Analysis ◽  
Macromolecular Complexes ◽  
Conformational Variability

Cryogenic electron tomography (cryo-ET) allows structural determination of biomolecules in their native environment (in situ). Its potential of providing information on the dynamics of macromolecular complexes in cells is still largely unexploited, due to the challenges of the data analysis. The crowded cell environment and continuous conformational changes of complexes make difficult disentangling the data heterogeneity. We present HEMNMA-3D, which is, to the best of our knowledge, the first method for analyzing cryo electron subtomograms in terms of continuous conformational changes of complexes. HEMNMA-3D uses a combination of elastic and rigid-body 3D-to-3D iterative alignments of a flexible 3D reference (atomic structure or electron microscopy density map) to match the conformation, orientation, and position of the complex in each subtomogram. The elastic matching combines molecular mechanics simulation (Normal Mode Analysis of the 3D reference) and experimental, subtomogram data analysis. The rigid-body alignment includes compensation for the missing wedge, due to the limited tilt angle of cryo-ET. The conformational parameters (amplitudes of normal modes) of the complexes in subtomograms obtained through the alignment are processed to visualize the distribution of conformations in a space of lower dimension (typically, 2D or 3D) referred to as space of conformations. This allows a visually interpretable insight into the dynamics of the complexes, by calculating 3D averages of subtomograms with similar conformations from selected (densest) regions and by recording movies of the 3D reference's displacement along selected trajectories through the densest regions. We describe HEMNMA-3D and show its validation using synthetic datasets. We apply HEMNMA-3D to an experimental dataset describing in situ nucleosome conformational variability. HEMNMA-3D software is available freely (open-source) as part of ContinuousFlex plugin of Scipion V3.0 (http://scipion.i2pc.es).

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