BRIDGE an open platform for reproducible high throughput free energy simulations
BRIDGE an open platform for reproducible high throughput free energy simulations
Biomolecular Reaction and Interaction Dynamics Global Environment (BRIDGE) is an open-source web platform developed with the aim to provide an environment for the design of reliable methods to conduct reproducible biomolecular simulations. It is built on the well-known Galaxy bioinformatics platform. Through this, BRIDGE hosts computational chemistry tools on public web servers for internet use and provides machine- and operating-system-independent portability using the Docker container platform for local use. This construction improves the accessibility, shareability, and reproducibility of computational methods for molecular simulations. Here we present integrated free energy tools (or apps) to calculate absolute binding free energies (ABFEs) and relative binding free energies (RBFEs), as illustrated through use cases. We present free energy perturbation (FEP) methods contained in various software packages such as GROMACS and YANK that are independent of hardware configuration, software libraries, or operating systems when ported in the Galaxy-BRIDGE Docker container platform. By performing cyclin-dependent kinase 2 (CDK2) FEP calculations on geographically dispersed web servers (in Africa and Europe), we illustrate that large-scale computations can be performed using the exact same codes and methodology by collaborating groups through publicly shared protocols and workflows. The ease of public sharing and independent reproduction of simulations via BRIDGE makes possible an open review of methods and complete simulation protocols. This makes the discovery of inhibitors for drug targets accessible to nonexperts and the computer experiments that are used to arrive at leads verifiable by experts and reviewers. We illustrate this on β-galactoside α-2,3-sialyltransferase I (ST3Gal-I), a breast cancer drug target, where a combination of RBFE and ABFE methods are used to compute the binding free energies of three inhibitors.
Chemical calculations, Galaxies, Inhibitors, free energy, ligands
5290-5295
Senapathi, Tharindu
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Suruzhon, Miroslav
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Barnett, Christopher B.
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Essex, Jonathan W.
1f409cfe-6ba4-42e2-a0ab-a931826314b5
Naidoo, Kevin J.
cad13bc7-b096-4c5d-b7a4-e4092e07dd3f
23 November 2020
Senapathi, Tharindu
b98b7c07-a1c4-4ef2-9d9a-b44d71b25e7b
Suruzhon, Miroslav
4ea4dd8b-0a98-4598-9eaa-756d943b5dca
Barnett, Christopher B.
77f80da6-e892-4bf5-841d-6d71b82b5b19
Essex, Jonathan W.
1f409cfe-6ba4-42e2-a0ab-a931826314b5
Naidoo, Kevin J.
cad13bc7-b096-4c5d-b7a4-e4092e07dd3f
Senapathi, Tharindu, Suruzhon, Miroslav, Barnett, Christopher B., Essex, Jonathan W. and Naidoo, Kevin J.
(2020)
BRIDGE an open platform for reproducible high throughput free energy simulations.
Journal of Chemical Information and Modeling, 60 (11), .
(doi:10.1021/acs.jcim.0c00206).
Abstract
Biomolecular Reaction and Interaction Dynamics Global Environment (BRIDGE) is an open-source web platform developed with the aim to provide an environment for the design of reliable methods to conduct reproducible biomolecular simulations. It is built on the well-known Galaxy bioinformatics platform. Through this, BRIDGE hosts computational chemistry tools on public web servers for internet use and provides machine- and operating-system-independent portability using the Docker container platform for local use. This construction improves the accessibility, shareability, and reproducibility of computational methods for molecular simulations. Here we present integrated free energy tools (or apps) to calculate absolute binding free energies (ABFEs) and relative binding free energies (RBFEs), as illustrated through use cases. We present free energy perturbation (FEP) methods contained in various software packages such as GROMACS and YANK that are independent of hardware configuration, software libraries, or operating systems when ported in the Galaxy-BRIDGE Docker container platform. By performing cyclin-dependent kinase 2 (CDK2) FEP calculations on geographically dispersed web servers (in Africa and Europe), we illustrate that large-scale computations can be performed using the exact same codes and methodology by collaborating groups through publicly shared protocols and workflows. The ease of public sharing and independent reproduction of simulations via BRIDGE makes possible an open review of methods and complete simulation protocols. This makes the discovery of inhibitors for drug targets accessible to nonexperts and the computer experiments that are used to arrive at leads verifiable by experts and reviewers. We illustrate this on β-galactoside α-2,3-sialyltransferase I (ST3Gal-I), a breast cancer drug target, where a combination of RBFE and ABFE methods are used to compute the binding free energies of three inhibitors.
Text
Main_ApplNote-BRIDGE-FE_JCIM_2020R3TC
- Accepted Manuscript
More information
e-pub ahead of print date: 18 August 2020
Published date: 23 November 2020
Additional Information:
Funding Information:
This work is based on research supported by the South African Research Chairs Initiative (SARChI) of the Department of Science and Technology (DST) and National Research Foundation (NRF) Grant 449130 and was supported by the South African Medical Research Council under a Self-Initiated Research Grant and a Medical Research Council (MRC) grant (K.J.N.). Even though the work was supported by the MRC, the views and opinions expressed are not those of the MRC but of the authors of the material produced or publicized. T.S. thanks SARChI for a doctoral award. We thank the Center for High Performance Computing for the use of their clusters. C.B.B. thanks the Univeristy of Cape Town for support. J.E. and M.S. thank AstraZeneca, GSK, and Syngenta for funding for this project. M.S. is grateful for the support from the EPSRC Centre for Doctoral Training, Theory and Modeling in Chemical Sciences under Grant EP/L015722/1.
Publisher Copyright:
© 2020 American Chemical Society.
Keywords:
Chemical calculations, Galaxies, Inhibitors, free energy, ligands
Identifiers
Local EPrints ID: 444424
URI: http://eprints.soton.ac.uk/id/eprint/444424
ISSN: 1549-9596
PURE UUID: bb7a1a82-a0b8-4cbc-a142-0cc30f2ae2e1
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Date deposited: 19 Oct 2020 16:31
Last modified: 17 Mar 2024 05:58
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Contributors
Author:
Tharindu Senapathi
Author:
Miroslav Suruzhon
Author:
Christopher B. Barnett
Author:
Kevin J. Naidoo
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