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

Christopher B. Barnett, Tharindu Senapathi and Kevin J. Naidoo

Beilstein J. Org. Chem. 2020, 16, 2540–2550. https://doi.org/10.3762/bjoc.16.206

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Supporting Information File 1: Additional molecular dynamics analyses.
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Comparative ligand structural analytics illustrated on variably glycosylated MUC1 antigen–antibody binding

Christopher B. Barnett, Tharindu Senapathi and Kevin J. Naidoo

Beilstein J. Org. Chem. 2020, 16, 2540–2550. https://doi.org/10.3762/bjoc.16.206

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Barnett, C. B.; Senapathi, T.; Naidoo, K. J. Beilstein J. Org. Chem. 2020, 16, 2540–2550. doi:10.3762/bjoc.16.206

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TY  - JOUR
A1  - Barnett, Christopher B.
A1  - Senapathi, Tharindu
A1  - Naidoo, Kevin J.
T1  - Comparative ligand structural analytics illustrated on variably glycosylated MUC1 antigen–antibody binding
JF  - Beilstein Journal of Organic Chemistry
PY  - 2020///
VL  - 16
SP  - 2540
EP  - 2550
SN  - 1860-5397
DO  - 10.3762/bjoc.16.206
PB  - Beilstein-Institut
JA  - Beilstein J. Org. Chem.
UR  - https://doi.org/10.3762/bjoc.16.206
KW  - binding
KW  - conformation
KW  - Galaxy
KW  - glycoprotein
KW  - in silico
N2  - 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.
ER  -

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Scholarly Works

Aoki-Kinoshita, K. F.; Lisacek, F.; Karlsson, N.; Kolarich, D.; Packer, N. H. GlycoBioinformatics. Beilstein journal of organic chemistry 2021, 17, 2726–2728. doi:10.3762/bjoc.17.184
Brockhausen, I.; Melamed, J. Mucins as anti-cancer targets: perspectives of the glycobiologist. Glycoconjugate journal 2021, 38, 459–474. doi:10.1007/s10719-021-09986-8

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