scholarly journals Molecular dynamics simulations disclose early stages of the photo-activation of cryptochrome 4

2018 ◽  
Author(s):  
D. R. Kattnig ◽  
C. Nielsen ◽  
I. A. Solov’yov
Keyword(s):  
Molecular Dynamics ◽  
Conformational Changes ◽  
Large Scale ◽  
Conformational Dynamics ◽  
Md Simulations ◽  
Quantum Processes ◽  
Helical Segment ◽  
High Betweenness ◽  
Dynamics Simulations ◽  
Fad Binding

AbstractBirds appear to be equipped with a light-dependent, radical-pair-based magnetic compass that relies on truly quantum processes. While the identity of the sensory protein has remained speculative, cryptochrome 4 has recently been identified as the most auspicious candidate. Here, we report on allatom molecular dynamics (MD) simulations addressing the structural reorganisations that accompany the photoreduction of the flavin cofactor in a model of the European robin cryptochrome 4 (ErCry4). Extensive MD simulations reveal that the photo-activation of ErCry4 induces large-scale conformational changes on short (hundreds of nanoseconds) timescales. Specifically, the photo-reduction is accompanied with the release of the C-terminal tail, structural rearrangements in the vicinity of the FAD-binding site, and the noteworthy formation of an α-helical segment at the N-terminal part. Some of these rearrangements appear to expose potential phosphorylation sites. We describe the conformational dynamics of the protein using a graph-based approach that is informed by the adjacency of residues and the correlation of their local motions. This approach reveals densely coupled reorganisation communities, which facilitate an efficient signal transduction due to a high density of hubs. These communities are interconnected by a small number of highly important residues characterized by high betweenness centrality. The network approach clearly identifies the sites restructuring upon photoactivation, which appear as protrusions or delicate bridges in the reorganisation network. We also find that, unlike in the homologous cryptochrome from D. melanogaster, the release of the C-terminal domain does not appear to be correlated with the transposition of a histidine residue close to the FAD cofactor.

Molecular Basis Explanation of Imatinib Resistance of Bcr-Abl Due to T315I and P-Loop Mutations from Molecular Dynamics Simulations.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2917-2917
Author(s):  
Tai-Sung Lee ◽  
Steven Potts ◽  
Hagop Kantarjian ◽  
Jorge Cortes ◽  
Francis Giles ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Conformational Changes ◽  
Electrostatic Interactions ◽  
Large Scale ◽  
Resistance Mechanism ◽  
Md Simulations ◽  
Resistance Mechanisms ◽  
Static Structure ◽  
Imatinib Resistance ◽  
Dynamics Simulations

Abstract Molecular dynamics (MD) simulations on the complex of imatinib with the wild-type, T315I, and other 10 P-loop mutants of the tyrosine kinase Bcr-Abl have been performed to study the imatinib resistance mechanism at the atomic level. MD simulations show that large scale computational simulations could offer insight information that a static structure or simple homology modeling methods cannot provide for studying the Bcr-Abl imatinib resistance problem, especially in the case of conformational changes due to remote mutations. By utilizing the Molecular Mechanics/Poisson-Boltzmann surface area (MM-PBSA) techniques and analyzing the interactions between imatinib and individual residues, imatinib resistance mechanisms not previously thought have been revealed. Non-directly contacted P-loop mutations either unfavorably change the direct electrostatic interactions with imatinib, or cause the conformational changes influencing the contact energies between imatinib and other non-P-loop residues. We demonstrate that imatinib resistance of T315I mainly comes from the breakdown of the interactions between imatinib and E286 and M290, contradictory to previously suggested that the missing hydrogen bonding is the main contribution. We also demonstrate that except for the mutations of the direct contact residues, such as L248 and Y253, the unfavorable electrostatic interaction between P-loop and imatinib is the main reason for resistance for the P-loop mutations. Furthermore, in Y255H, protonation of the histidin is essential for rendering this mutation resistant to Gleevec. Our results demonstrate that MD is a powerful way to verify and predict clinical response or resistance to imatinib and other potential drugs.

Molecular Basis of Glucose Transport Mechanism in Plants

2019 ◽  
Author(s):  
Balaji Selvam ◽  
Ya-Chi Yu ◽  
Liqing Chen ◽  
Diwakar Shukla
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Dynamics Simulations ◽  
Conformational Changes ◽  
Transport Mechanism ◽  
Conformational Dynamics ◽  
Site Directed Mutagenesis ◽  
Free Energy Barrier ◽  
Transport Cycle ◽  
Dynamics Simulations

<p>The SWEET family belongs to a class of transporters in plants that undergoes large conformational changes to facilitate transport of sugar molecules across the cell membrane. However, the structures of their functionally relevant conformational states in the transport cycle have not been reported. In this study, we have characterized the conformational dynamics and complete transport cycle of glucose in OsSWEET2b transporter using extensive molecular dynamics simulations. Using Markov state models, we estimated the free energy barrier associated with different states as well as 1 for the glucose the transport mechanism. SWEETs undergoes structural transition to outward-facing (OF), Occluded (OC) and inward-facing (IF) and strongly support alternate access transport mechanism. The glucose diffuses freely from outside to inside the cell without causing major conformational changes which means that the conformations of glucose unbound and bound snapshots are exactly same for OF, OC and IF states. We identified a network of hydrophobic core residues at the center of the transporter that restricts the glucose entry to the cytoplasmic side and act as an intracellular hydrophobic gate. The mechanistic predictions from molecular dynamics simulations are validated using site-directed mutagenesis experiments. Our simulation also revealed hourglass like intermediate states making the pore radius narrower at the center. This work provides new fundamental insights into how substrate-transporter interactions actively change the free energy landscape of the transport cycle to facilitate enhanced transport activity.</p>

scholarly journals A Virtual Reality Ensemble Molecular Dynamics Workflow to Study Complex Conformational Changes in Proteins

2020 ◽  
Author(s):  
Jordi Juárez-Jiménez ◽  
Philip Tew ◽  
Michael o'connor ◽  
Salome Llabres ◽  
Rebecca Sage ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Virtual Reality ◽  
Conformational Changes ◽  
Large Scale ◽  
A Priori ◽  
Computational Cost ◽  
Md Simulations ◽  
Collective Variables ◽  
Sampling Protocols ◽  
State Models

<p>Molecular dynamics (MD) simulations are increasingly used to elucidate relationships between protein structure, dynamics and their biological function. Currently it is extremely challenging to perform MD simulations of large-scale structural rearrangements in proteins that occur on millisecond timescales or beyond, as this requires very significant computational resources, or the use of cumbersome ‘collective variable’ enhanced sampling protocols. Here we describe a framework that combines ensemble MD simulations and virtual-reality visualization (eMD-VR) to enable users to interactively generate realistic descriptions of large amplitude, millisecond timescale protein conformational changes in proteins. Detailed tests demonstrate that eMD-VR substantially decreases the computational cost of folding simulations of a WW domain, without the need to define collective variables <i>a priori</i>. We further show that eMD-VR generated pathways can be combined with Markov State Models to describe the thermodynamics and kinetics of large-scale loop motions in the enzyme cyclophilin A. Our results suggest eMD-VR is a powerful tool for exploring protein energy landscapes in bioengineering efforts. </p>

scholarly journals Visual Analytics for Deep Embeddings of Large Scale Molecular Dynamics Simulations

2019 ◽  
Author(s):  
Junghoon Chae ◽  
Debsindhu Bhowmik ◽  
Heng Ma ◽  
Arvind Ramanathan ◽  
Chad Steed
Keyword(s):  
Molecular Dynamics ◽  
Visual Analytics ◽  
Large Scale ◽  
Physical Phenomenon ◽  
Living Organism ◽  
Md Simulations ◽  
High Dimensional ◽  
Molecular Characteristics ◽  
Complex Simulation ◽  
Dynamics Simulations

AbstractMolecular Dynamics (MD) simulation have been emerging as an excellent candidate for understanding complex atomic and molecular scale mechanism of bio-molecules that control essential bio-physical phenomenon in a living organism. But this MD technique produces large-size and long-timescale data that are inherently high-dimensional and occupies many terabytes of data. Processing this immense amount of data in a meaningful way is becoming increasingly difficult. Therefore, specific dimensionality reduction algorithm using deep learning technique has been employed here to embed the high-dimensional data in a lower-dimension latent space that still preserves the inherent molecular characteristics i.e. retains biologically meaningful information. Subsequently, the results of the embedding models are visualized for model evaluation and analysis of the extracted underlying features. However, most of the existing visualizations for embeddings have limitations in evaluating the embedding models and understanding the complex simulation data. We propose an interactive visual analytics system for embeddings of MD simulations to not only evaluate and explain an embedding model but also analyze various characteristics of the simulations. Our system enables exploration and discovery of meaningful and semantic embedding results and supports the understanding and evaluation of results by the quantitatively described features of the MD simulations (even without specific labels).

scholarly journals Combining Virtual Reality Visualization with Ensemble Molecular Dynamics to Study Complex Protein Conformational Changes

2020 ◽  
Author(s):  
Jordi Juárez-Jiménez ◽  
Philip Tew ◽  
Michael o'connor ◽  
Salome Llabres ◽  
Rebecca Sage ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Virtual Reality ◽  
Conformational Changes ◽  
Large Scale ◽  
Computational Cost ◽  
Md Simulations ◽  
Collective Variables ◽  
Protein Conformational Changes ◽  
Sampling Protocols ◽  
State Models

<p>Molecular dynamics (MD) simulations are increasingly used to elucidate relationships between protein structure, dynamics and their biological function. Currently it is extremely challenging to perform MD simulations of large-scale structural rearrangements in proteins that occur on millisecond timescales or beyond, as this requires very significant computational resources, or the use of cumbersome ‘collective variable’ enhanced sampling protocols. Here we describe a framework that combines ensemble MD simulations and virtual-reality visualization (eMD-VR) to enable users to interactively generate realistic descriptions of large amplitude, millisecond timescale protein conformational changes in proteins. Detailed tests demonstrate that eMD-VR substantially decreases the computational cost of folding simulations of a WW domain, without the need to define collective variables <i>a priori</i>. We further show that eMD-VR generated pathways can be combined with Markov State Models to describe the thermodynamics and kinetics of large-scale loop motions in the enzyme cyclophilin A. Our results suggest eMD-VR is a powerful tool for exploring protein energy landscapes in bioengineering efforts. </p>

Molecular Basis of Glucose Transport Mechanism in Plants

2019 ◽  
Author(s):  
Balaji Selvam ◽  
Ya-Chi Yu ◽  
Liqing Chen ◽  
Diwakar Shukla
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Dynamics Simulations ◽  
Conformational Changes ◽  
Transport Mechanism ◽  
Conformational Dynamics ◽  
Site Directed Mutagenesis ◽  
Free Energy Barrier ◽  
Transport Cycle ◽  
Dynamics Simulations

<p>The SWEET family belongs to a class of transporters in plants that undergoes large conformational changes to facilitate transport of sugar molecules across the cell membrane. However, the structures of their functionally relevant conformational states in the transport cycle have not been reported. In this study, we have characterized the conformational dynamics and complete transport cycle of glucose in OsSWEET2b transporter using extensive molecular dynamics simulations. Using Markov state models, we estimated the free energy barrier associated with different states as well as 1 for the glucose the transport mechanism. SWEETs undergoes structural transition to outward-facing (OF), Occluded (OC) and inward-facing (IF) and strongly support alternate access transport mechanism. The glucose diffuses freely from outside to inside the cell without causing major conformational changes which means that the conformations of glucose unbound and bound snapshots are exactly same for OF, OC and IF states. We identified a network of hydrophobic core residues at the center of the transporter that restricts the glucose entry to the cytoplasmic side and act as an intracellular hydrophobic gate. The mechanistic predictions from molecular dynamics simulations are validated using site-directed mutagenesis experiments. Our simulation also revealed hourglass like intermediate states making the pore radius narrower at the center. This work provides new fundamental insights into how substrate-transporter interactions actively change the free energy landscape of the transport cycle to facilitate enhanced transport activity.</p>

scholarly journals Effects of number of parallel runs and frequency of bias-strength replacement in generalized ensemble molecular dynamics simulations

2019 ◽  
Vol 1 ◽  
pp. e4 ◽  
Author(s):  
Takuya Shimato ◽  
Kota Kasahara ◽  
Junichi Higo ◽  
Takuya Takahashi
Keyword(s):  
Molecular Dynamics ◽  
Potential Energy ◽  
Molecular Dynamics Simulations ◽  
Conformational Changes ◽  
High Frequency ◽  
Md Simulations ◽  
Energy Space ◽  
Bias Potential ◽  
Ensemble Approach ◽  
Dynamics Simulations

Background The generalized ensemble approach with the molecular dynamics (MD) method has been widely utilized. This approach usually has two features. (i) A bias potential, whose strength is replaced during a simulation, is applied. (ii) Sampling can be performed by many parallel runs of simulations. Although the frequency of the bias-strength replacement and the number of parallel runs can be adjusted, the effects of these settings on the resultant ensemble remain unclear. Method In this study, we performed multicanonical MD simulations for a foldable mini-protein (Trp-cage) and two unstructured peptides (8- and 20-residue poly-glutamic acids) with various settings. Results As a result, running many short simulations yielded robust results for the Trp-cage model. Regarding the frequency of the bias-potential replacement, although using a high frequency enhanced the traversals in the potential energy space, it did not promote conformational changes in all the systems.

scholarly journals Combining Virtual Reality Visualization with Ensemble Molecular Dynamics to Study Complex Protein Conformational Changes

2020 ◽  
Author(s):  
Jordi Juárez-Jiménez ◽  
Philip Tew ◽  
Michael o'connor ◽  
Salome Llabres ◽  
Rebecca Sage ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Virtual Reality ◽  
Conformational Changes ◽  
Large Scale ◽  
Computational Cost ◽  
Md Simulations ◽  
Collective Variables ◽  
Protein Conformational Changes ◽  
Sampling Protocols ◽  
State Models

<p>Molecular dynamics (MD) simulations are increasingly used to elucidate relationships between protein structure, dynamics and their biological function. Currently it is extremely challenging to perform MD simulations of large-scale structural rearrangements in proteins that occur on millisecond timescales or beyond, as this requires very significant computational resources, or the use of cumbersome ‘collective variable’ enhanced sampling protocols. Here we describe a framework that combines ensemble MD simulations and virtual-reality visualization (eMD-VR) to enable users to interactively generate realistic descriptions of large amplitude, millisecond timescale protein conformational changes in proteins. Detailed tests demonstrate that eMD-VR substantially decreases the computational cost of folding simulations of a WW domain, without the need to define collective variables <i>a priori</i>. We further show that eMD-VR generated pathways can be combined with Markov State Models to describe the thermodynamics and kinetics of large-scale loop motions in the enzyme cyclophilin A. Our results suggest eMD-VR is a powerful tool for exploring protein energy landscapes in bioengineering efforts. </p>

scholarly journals Insights from Molecular Dynamics Simulations for GPCR Drug Discovery

2019 ◽  
Author(s):  
Ye Zou ◽  
John Ewalt ◽  
Ho-Leung Ng
Keyword(s):  
Molecular Dynamics ◽  
Drug Discovery ◽  
G Protein ◽  
Drug Targets ◽  
Conformational Dynamics ◽  
Md Simulations ◽  
Protein Activation ◽  
Downstream Signaling ◽  
Dynamics Simulations ◽  
G Protein Coupled

G protein-coupled receptors (GPCRs) are critical drug targets. GPCRs convey signals from the extracellular to the intracellular environment through G proteins. There is evidence that some ligands that bind to the GPCRs activate different downstream signaling pathways. G protein activation or -arrestin biased signaling involves ligands binding to receptors and stabilizing conformations that trigger a specific pathway. Molecular dynamics (MD) simulations are especially valuable for obtaining detailed mechanistic information, including identification of allosteric sites and understanding modulators' interactions between receptors and ligands. Here, we highlight recent simulation studies and methods used to study biased G protein-coupled receptor signaling and their conformational dynamics. We also highlight applications of MD simulations to drug discovery.

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