Intuitive, reproducible high-throughput molecular dynamics in Galaxy: a tutorial

Bray, Simon; Senapathi, Tharindu; Barnett, Christopher B.; Grüning, Björn

doi:10.1101/2020.05.08.084780

Cited by 3 publications

(1 citation statement)

References 30 publications

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“…The root-mean-square deviation (RMSD) is calculated to measure the stability and conformation of a set of selected atoms. The RMSD is a standard measure of the structural distance between coordinate sets that measures the average distance between a group of atoms [ 40 ]. The peptide portion of the antigens was selected for analysis.…”

Section: Methodsmentioning

confidence: 99%

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

Barnett¹,

Senapathi²,

Naidoo³

2020

Beilstein J. Org. Chem.

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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.

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Section: Methodsmentioning

confidence: 99%

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

Barnett¹,

Senapathi²,

Naidoo³

2020

Beilstein J. Org. Chem.

Self Cite

View full text Add to dashboard Cite

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Functional characterization of novel mutations in the conserved region of EPSPS for herbicide resistance in pigeonpea: structure-based coherent design

Bharti,

Verma,

Gupta

et al. 2023

Journal of Biomolecular Structure and Dynamics

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MOLECULAR DYNAMICS SIMULATION OF FOUR BIFLAVONOIDS WITH THE LEISHMANOLYSIN (gp63) PROTEIN OF Leishmania major

Mercado-Camargo

Cervantes-Ceballos

Vivas‐Reyes

et al. 2022

Preprint

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Leishmanolisyn (gp63) is a 63 kDa surface metalloprotease belonging to the M8 family (subclan MA (M), metzincines) that is found in both promastigote and amastigote of leishmania ssp. It constitutes one of the virulence factors in the pathogenesis of Leishmania spp., being crucial in its entry into the macrophage and in complement activation. Therefore, gp63 may be a therapeutic alternative for potential new drugs needed to combat this disease. Among the many functional groups of naturally occurring compounds, the biflavonoids amentoflavone (A), lanaraflavone (L), podocarpusflavone A (PA), and podocarpusflovone B (PB) are promising candidate ligands for the treatment of all forms of leishmaniasis. In this study we carried out the validated molecular dynamics simulation with GROMACS, using mean square deviation (RMSD), mean square fluctuation (RMSF), the radius of gyration (Rg), and intermolecular hydrogen bonds (H-bonds) between the gp63 protein of L. major (1LML) in complex with the four biflavonoids. In addition, the free binding energies were estimated using the MM-PBSA method, to determine their stability in the active site of the protein. The computational analysis revealed that the interaction of lanaroflavone (ΔGBing = -156.75 ± 31.91 Kcal/mol for L. major) remained stable in this enzyme, revealing their remarkable potential as a possible antileishmanial agent to combat the Leishmania parasite. On the other hand, amentoflavone, podocarpusflavone A, and B also showed a good affinity for both metalloproteases according to the ΔGbind values obtained.

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Intuitive, reproducible high-throughput molecular dynamics in Galaxy: a tutorial

Cited by 3 publications

References 30 publications

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

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

Functional characterization of novel mutations in the conserved region of EPSPS for herbicide resistance in pigeonpea: structure-based coherent design

MOLECULAR DYNAMICS SIMULATION OF FOUR BIFLAVONOIDS WITH THE LEISHMANOLYSIN (gp63) PROTEIN OF Leishmania major

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