Title: Free energy along drug-protein binding pathways interactively sampled in virtual reality

Authors (6): H. M. Deeks, K. Zinovjev, J. Barnoud, A. J. Mulholland, M. W. van der Kamp, D. R. Glowacki

Themes: New Catalysts (2023), Water-Energy (2023), Circular Economy (2023), Core (2023)

DOI: 10.1038/s41598-023-43523-x

Citations: 1

Pub type: journal-article

Publisher: Springer Science and Business Media LLC

Issue: 1

License: [{"start"=>{"date-parts"=>[[2023, 10, 4]], "date-time"=>"2023-10-04T00:00:00Z", "timestamp"=>1696377600000}, "content-version"=>"tdm", "delay-in-days"=>0, "URL"=>"https://creativecommons.org/licenses/by/4.0"}, {"start"=>{"date-parts"=>[[2023, 10, 4]], "date-time"=>"2023-10-04T00:00:00Z", "timestamp"=>1696377600000}, "content-version"=>"vor", "delay-in-days"=>0, "URL"=>"https://creativecommons.org/licenses/by/4.0"}]

Publication date(s): 2023/10/04 (online)

Pages:

Volume: 13 Issue: 1

Journal: Scientific Reports

Link: [{"URL"=>"https://www.nature.com/articles/s41598-023-43523-x.pdf", "content-type"=>"application/pdf", "content-version"=>"vor", "intended-application"=>"text-mining"}, {"URL"=>"https://www.nature.com/articles/s41598-023-43523-x", "content-type"=>"text/html", "content-version"=>"vor", "intended-application"=>"text-mining"}, {"URL"=>"https://www.nature.com/articles/s41598-023-43523-x.pdf", "content-type"=>"application/pdf", "content-version"=>"vor", "intended-application"=>"similarity-checking"}]

URL: http://dx.doi.org/10.1038/s41598-023-43523-x

AbstractWe describe a two-step approach for combining interactive molecular dynamics in virtual reality (iMD-VR) with free energy (FE) calculation to explore the dynamics of biological processes at the molecular level. We refer to this combined approach as iMD-VR-FE. Stage one involves using a state-of-the-art ‘human-in-the-loop’ iMD-VR framework to generate a diverse range of protein–ligand unbinding pathways, benefitting from the sophistication of human spatial and chemical intuition. Stage two involves using the iMD-VR-sampled pathways as initial guesses for defining a path-based reaction coordinate from which we can obtain a corresponding free energy profile using FE methods. To investigate the performance of the method, we apply iMD-VR-FE to investigate the unbinding of a benzamidine ligand from a trypsin protein. The binding free energy calculated using iMD-VR-FE is similar for each pathway, indicating internal consistency. Moreover, the resulting free energy profiles can distinguish energetic differences between pathways corresponding to various protein–ligand conformations (e.g., helping to identify pathways that are more favourable) and enable identification of metastable states along the pathways. The two-step iMD-VR-FE approach offers an intuitive way for researchers to test hypotheses for candidate pathways in biomolecular systems, quickly obtaining both qualitative and quantitative insight.

Name Description Publised
Free energy for drug-protein binding from human-guided atomistic simulations in virtual reality - Supplementary Files iMD-VR trajectories, narupa inputs, system parameters, and umbrella samp... 2022
Narupa 2 Protocol The programs necessary for running a standalone simulation of trypsin an... 2022
41598_2023_43523_MOESM1_ESM.pdf Free energy along drug-protein binding pathways interactively sampled in... 2023


Back