Dakka, J;
Turilli, M;
Wright, DW;
Zasada, SJ;
Balasubramanian, V;
Wan, S;
Coveney, PV;
(2018)
High-throughput binding affinity calculations at extreme scales.
BMC Bioinformatics
, 19
(Suppl 18)
, Article 482. 10.1186/s12859-018-2506-6.
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Abstract
BACKGROUND: Resistance to chemotherapy and molecularly targeted therapies is a major factor in limiting the effectiveness of cancer treatment. In many cases, resistance can be linked to genetic changes in target proteins, either pre-existing or evolutionarily selected during treatment. Key to overcoming this challenge is an understanding of the molecular determinants of drug binding. Using multi-stage pipelines of molecular simulations we can gain insights into the binding free energy and the residence time of a ligand, which can inform both stratified and personal treatment regimes and drug development. To support the scalable, adaptive and automated calculation of the binding free energy on high-performance computing resources, we introduce the High-throughput Binding Affinity Calculator (HTBAC). HTBAC uses a building block approach in order to attain both workflow flexibility and performance. RESULTS: We demonstrate close to perfect weak scaling to hundreds of concurrent multi-stage binding affinity calculation pipelines. This permits a rapid time-to-solution that is essentially invariant of the calculation protocol, size of candidate ligands and number of ensemble simulations. CONCLUSIONS: As such, HTBAC advances the state of the art of binding affinity calculations and protocols. HTBAC provides the platform to enable scientists to study a wide range of cancer drugs and candidate ligands in order to support personalized clinical decision making based on genome sequencing and drug discovery.
| Type: | Article |
|---|---|
| Title: | High-throughput binding affinity calculations at extreme scales |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1186/s12859-018-2506-6 |
| Publisher version: | https://doi.org/10.1186/s12859-018-2506-6 |
| Language: | English |
| Additional information: | Copyright © The Author(s). This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/ licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/ 1.0/) applies to the data made available in this article, unless otherwise stated. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > UCL BEAMS UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10064861 |
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