scholarly journals Comparative ligand structural analytics illustrated on variably glycosylated MUC1 antigen–antibody binding

2020 ◽  
Vol 16 ◽  
pp. 2540-2550
Author(s):  
Christopher B Barnett ◽  
Tharindu Senapathi ◽  
Kevin J Naidoo
Keyword(s):  
Visual Analysis ◽  
Dynamic Structure ◽  
Structural Data ◽  
General Strategy ◽  
Trajectory Data ◽  
Mucin 1 ◽  
The Galaxy ◽  
End Distance ◽  
Key Features ◽  
Dynamics Simulations

When faced with the investigation of the preferential binding of a series of ligands against a known target, the solution is not always evident from single structure analysis. An ensemble of structures generated from computer simulations is valuable; however, visual analysis of the extensive structural data can be overwhelming. Rapid analysis of trajectory data, with tools available in the Galaxy platform, can be used to understand key features and compare differences that inform the preferential ligand structure that favors binding. We illustrate this informatics approach by investigating the in-silico binding of a peptide and glycopeptide epitope of the glycoprotein Mucin 1 (MUC1) binding with the antibody AR20.5. To study the binding, we performed molecular dynamics simulations using OpenMM and then used the Galaxy platform for data analysis. The same analysis tools are applied to each of the simulation trajectories and this process was streamlined by using Galaxy workflows. The conformations of the antigens were analyzed using root-mean-square deviation, end-to-end distance, Ramachandran plots, and hydrogen bonding analysis. Additionally, RMSF and clustering analysis were carried out. These analyses were used to rapidly assess key features of the system, interrogate the dynamic structure of the ligand, and determine the role of glycosylation on the conformational equilibrium. The glycopeptide conformations in solution change relative to the peptide; thus a partially pre-structuring is seen prior to binding. Although the bound conformation of peptide and glycopeptide is similar, the glycopeptide fluctuates less and resides in specific conformers for more extended periods. This structural analysis which gives a high-level view of the features in the system under observation, could be readily applied to other binding problems as part of a general strategy in drug design or mechanistic analysis.

scholarly journals Studies of Conformational Changes of Tubulin Induced by Interaction with Kinesin Using Atomistic Molecular Dynamics Simulations

2021 ◽  
Vol 22 (13) ◽  
pp. 6709
Author(s):  
Xiao-Xuan Shi ◽  
Peng-Ye Wang ◽  
Hong Chen ◽  
Ping Xie
Keyword(s):  
Molecular Dynamics ◽  
High Resolution ◽  
Binding Energy ◽  
Molecular Dynamics Simulations ◽  
Conformational Changes ◽  
Weak Interactions ◽  
Molecular Motor ◽  
Structural Data ◽  
Calculated Binding Energy ◽  
Dynamics Simulations

The transition between strong and weak interactions of the kinesin head with the microtubule, which is regulated by the change of the nucleotide state of the head, is indispensable for the processive motion of the kinesin molecular motor on the microtubule. Here, using all-atom molecular dynamics simulations, the interactions between the kinesin head and tubulin are studied on the basis of the available high-resolution structural data. We found that the strong interaction can induce rapid large conformational changes of the tubulin, whereas the weak interaction cannot. Furthermore, we found that the large conformational changes of the tubulin have a significant effect on the interaction of the tubulin with the head in the weak-microtubule-binding ADP state. The calculated binding energy of the ADP-bound head to the tubulin with the large conformational changes is only about half that of the tubulin without the conformational changes.

scholarly journals Response to Comment on “Structural evidence for a dynamic metallocofactor during N2 reduction by Mo-nitrogenase”

Science ◽  
2021 ◽  
Vol 371 (6530) ◽  
pp. eabe5856
Author(s):  
Wonchull Kang ◽  
Chi Chung Lee ◽  
Andrew J. Jasniewski ◽  
Markus W. Ribbe ◽  
Yilin Hu
Keyword(s):  
Dynamic Structure ◽  
Structural Data ◽  
Biochemical Data ◽  
Structural Refinement

Peters et al. comment on our report of the dynamic structure of the nitrogenase metallocofactor during N2 reduction. Their claim that their independent structural refinement and consideration of biochemical data contradict our finding is incorrect and is strongly refuted by our biochemical and structural data that collectively and conclusively point to the binding of dinitrogen species to the nitrogenase cofactor.

Crystal structure of the wild-type and D30A mutant thioredoxin h of Chlamydomonas reinhardtii and implications for the catalytic mechanism

2001 ◽  
Vol 359 (1) ◽  
pp. 65-75 ◽  
Author(s):  
Valeria MENCHISE ◽  
Catherine CORBIER ◽  
Claude DIDIERJEAN ◽  
Michele SAVIANO ◽  
Ettore BENEDETTI ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Proton Transfer ◽  
Chlamydomonas Reinhardtii ◽  
Catalytic Mechanism ◽  
Structural Data ◽  
Careful Analysis ◽  
Wild Type ◽  
Thioredoxin H ◽  
Dynamics Simulations

Thioredoxins are ubiquitous proteins which catalyse the reduction of disulphide bridges on target proteins. The catalytic mechanism proceeds via a mixed disulphide intermediate whose breakdown should be enhanced by the involvement of a conserved buried residue, Asp-30, as a base catalyst towards residue Cys-39. We report here the crystal structure of wild-type and D30A mutant thioredoxin h from Chlamydomonas reinhardtii, which constitutes the first crystal structure of a cytosolic thioredoxin isolated from a eukaryotic plant organism. The role of residue Asp-30 in catalysis has been revisited since the distance between the carboxylate OD1 of Asp-30 and the sulphur SG of Cys-39 is too great to support the hypothesis of direct proton transfer. A careful analysis of all available crystal structures reveals that the relative positioning of residues Asp-30 and Cys-39 as well as hydrophobic contacts in the vicinity of residue Asp-30 do not allow a conformational change sufficient to bring the two residues close enough for a direct proton transfer. This suggests that protonation/deprotonation of Cys-39 should be mediated by a water molecule. Molecular-dynamics simulations, carried out either in vacuo or in water, as well as proton-inventory experiments, support this hypothesis. The results are discussed with respect to biochemical and structural data.

scholarly journals Microscopic Visual Analysis of High-Density Group Trajectory Data

2020 ◽  
Vol 32 (12) ◽  
pp. 1871-1880
Author(s):  
Sujia Zhu ◽  
Guodao Sun ◽  
Qi Jiang ◽  
Wang Xia ◽  
Ronghua Liang
Keyword(s):  
Visual Analysis ◽  
High Density ◽  
Trajectory Data

scholarly journals Molecular Determinants of μ-Conotoxin KIIIA Interaction with the Voltage-Gated Sodium Channel Nav1.7

2019 ◽  
Author(s):  
Ian H. Kimball ◽  
Phuong T. Nguyen ◽  
Baldomero M. Olivera ◽  
Jon T. Sack ◽  
Vladimir Yarov-Yarovoy
Keyword(s):  
Computational Modeling ◽  
Rational Design ◽  
Structural Model ◽  
Critical Role ◽  
Structural Data ◽  
Molecular Probes ◽  
Integrative Approach ◽  
In Silico Docking ◽  
Voltage Gated ◽  
Dynamics Simulations

AbstractThe voltage-gated sodium (Nav) channel subtype Nav1.7 plays a critical role in pain signaling, making it an important drug target. Here we studied the molecular interactions between μ-conotoxin KIIIA (KIIIA) and the human Nav1.7 channel (hNav1.7). We developed a structural model of hNav1.7 using Rosetta computational modeling and performed in silico docking of KIIIA using RosettaDock to predict residues forming specific pairwise contacts between KIIIA and hNav1.7. We experimentally validated these contacts using mutant cycle analysis. Comparison between our KIIIA-hNav1.7 model and the recently published cryo-EM structure of KIIIA-hNav1.2 revealed key similarities and differences between channel subtypes with potential implications for the molecular mechanism of toxin block. Our integrative approach, combining structural data with computational modeling, experimental validation, and molecular dynamics simulations will be useful for engineering molecular probes to study Nav channel function, and for rational design of novel biologics targeting specific Nav channels.

scholarly journals Enlighten2: molecular dynamics simulations of protein–ligand systems made accessible

2020 ◽  
Vol 36 (20) ◽  
pp. 5104-5106
Author(s):  
Kirill Zinovjev ◽  
Marc W van der Kamp
Keyword(s):  
Molecular Dynamics ◽  
Expert Knowledge ◽  
Structural Data ◽  
Md Simulations ◽  
Enzyme Engineering ◽  
Protein Ligand Interactions ◽  
Ligand Interactions ◽  
Dynamics Simulations ◽  
User Friendly ◽  
Dynamical Information

Abstract Motivation Experimental structural data can allow detailed insight into protein structure and protein–ligand interactions, which is crucial for many areas of bioscience, including drug design and enzyme engineering. Typically, however, little more than a static picture of protein–ligand interactions is obtained, whereas dynamical information is often required for deeper understanding and to assess the effect of mutations. Molecular dynamics (MD) simulations can provide such information, but setting up and running these simulations is not straightforward and requires expert knowledge. There is thus a need for a tool that makes protein–ligand simulation easily accessible to non-expert users. Results We present Enlighten2: efficient simulation protocols for protein–ligand systems alongside a user-friendly plugin to the popular visualization program PyMOL. With Enlighten2, non-expert users can straightforwardly run and visualize MD simulations on protein–ligand models of interest. There is no need to learn new programs and all underlying tools are free and open source. Availability and implementation The Enlighten2 Python package and PyMOL plugin are free to use under the GPL3.0 licence and can be found at https://enlighten2.github.io. We also provide a lightweight Docker image via DockerHub that includes Enlighten2 with all the required utilities.

scholarly journals West Lake Tourist: A Visual Analysis System Based on Taxi Data

Smart Cities ◽  
2019 ◽  
Vol 2 (3) ◽  
pp. 345-358 ◽  
Author(s):  
Jiang ◽  
Cao ◽  
Liu ◽  
Fan
Keyword(s):  
Domain Knowledge ◽  
Visual Analysis ◽  
Route Planning ◽  
Trajectory Data ◽  
West Lake ◽  
Point Of Interest ◽  
Scenic Spot ◽  
City Construction ◽  
Analysis System

Mining the mobile pattern of the urban population plays an important role in city construction, and visual analysis is a powerful technique in studying mobile patterns. In this paper, based on the taxi trajectory data in Hangzhou, we share our design for an interactive visual analytic system, which helps analyzers leverage their domain knowledge to gain insight into travel patterns, including travel time rules of tourists and the distribution rules of pick-up and drop-off locations. Besides, our system can present the dynamic travel process and the Point of Interest (POIs) information of the origin and the destination. A case study has been conducted, which verifies that our system can provide tools for urban managers or urban experts on the design of scenic spot open entrances and exits and travel route planning.

scholarly journals Optimizing the performance of reactive molecular dynamics simulations for many-core architectures

2018 ◽  
Vol 33 (2) ◽  
pp. 304-321 ◽  
Author(s):  
Hasan Metin Aktulga ◽  
Chris Knight ◽  
Paul Coffman ◽  
Kurt A O’Hearn ◽  
Tzu-Ray Shan ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Molecular Species ◽  
Trajectory Data ◽  
Reactive Molecular Dynamics ◽  
Species Analysis ◽  
Dynamics Simulations ◽  
Many Core ◽  
Molecular Species Analysis

Reactive molecular dynamics simulations are computationally demanding. Reaching spatial and temporal scales where interesting scientific phenomena can be observed requires efficient and scalable implementations on modern hardware. In this article, we focus on optimizing the performance of the widely used LAMMPS/ReaxC package for many-core architectures. As hybrid parallelism allows better leverage of the increasing on-node parallelism, we adopt thread parallelism in the construction of bonded and nonbonded lists and in the computation of complex ReaxFF interactions. To mitigate the I/O overheads due to large volumes of trajectory data produced and to save users the burden of post-processing, we also develop a novel in situ tool for molecular species analysis. We analyze the performance of the resulting ReaxC-OMP package on two different architectures: (i) Mira, an IBM Blue Gene/Q system and (ii) Cori-II, a Cray XC-40 sytem with Knights Landing processors. For Pentaerythritol tetranitrate (PETN) systems of sizes ranging from 32 thousand to 16.6 million particles, we observe speedups in the range of 1.5–4.5×. We observe sustained performance improvements for up to 262,144 cores (1,048,576 processes) of Mira and a weak scaling efficiency of 91.5% in large simulations containing 16.6 million particles. The in situ molecular species analysis tool incurs only insignificant overheads across various system sizes and runs configurations.

scholarly journals NRas slows the rate at which a model lipid bilayer phase separates

2014 ◽  
Vol 169 ◽  
pp. 209-223 ◽  
Author(s):  
Elizabeth Jefferys ◽  
Mark S. P. Sansom ◽  
Philip W. Fowler
Keyword(s):  
Lipid Bilayer ◽  
Cell Signalling ◽  
Line Tension ◽  
Structural Data ◽  
Coarse Grained ◽  
Ras Proteins ◽  
C Terminus ◽  
Ras Family ◽  
Multiple Copies ◽  
Dynamics Simulations

The Ras family of small membrane-associated GTP-ases are important components in many different cell signalling cascades. They are thought to cluster on the cell membrane through association with cholesterol-rich nanodomains. This process remains poorly understood. Here we test the effect of adding multiple copies of NRas, one of the canonical Ras proteins, to a three-component lipid bilayer that rapidly undergoes spinodal decomposition (i.e.unmixing), thereby creating ordered and disordered phases. Coarse-grained molecular dynamics simulations of a large bilayer containing 6000 lipids, with and without protein, are compared. NRas preferentially localises to the interface between the domains and slows the rate at which the domains grow. We infer that this doubly-lipidated cell signalling protein is reducing the line tension between the ordered and disordered regions. This analysis is facilitated by our use of techniques borrowed from image-processing. The conclusions above are contingent upon several assumptions, including the use of a model lipid with doubly unsaturated tails and the limited structural data available for the C-terminus of NRas, which is where the lipid anchors are found.

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